Uterine and Placental KISS1 Regulate Pregnancy: What We Know and The

REPRODUCTIONREVIEW

Transcriptional regulators of the trophoblast lineage in mammals with hemochorial placentation

Jason G Knott and Soumen Paul1 Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, Michigan 48824, USA and 1Department of Pathology and Laboratory Medicine, Institute of Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA Correspondence should be addressed to S Paul; Email: [email protected]

Abstract

Mammalian reproduction is critically dependent on the trophoblast cell lineage, which assures proper establishment of maternal–fetal interactions during pregnancy. Specification of trophoblast cell lineage begins with the development of the trophectoderm (TE) in preimplantation embryos. Subsequently, other trophoblast cell types arise with the progression of pregnancy. Studies with transgenic animal models as well as trophoblast stem/progenitor cells have implicated distinct transcriptional and epigenetic regulators in trophoblast lineage development. This review focuses on our current understanding of transcriptional and epigenetic mechanisms regulating specification, determination, maintenance and differentiation of trophoblast cells. Reproduction (2014) 148 R121–R136

Introduction human trophoblast development is restricted due to ethical reasons and lack of proper model systems. Thus, Mammalian reproduction is uniquely characterized the majority of our understanding of transcriptional by the formation of the placenta, a transient extraem- mechanisms that regulate trophoblast development bryonic organ that mediates dynamic interaction comes from studies in rodent models. between embryonic and maternal tissues and ensures Humans possess hemochorial placenta, in which the successful development of the embryo proper. This maternal blood is in direct contact with chorionic intimate relationship between the embryo and mother trophoblast cells, thereby facilitating nutrient exchanges is crucially dependent upon trophoblast cells as they between mother and the fetus. Interestingly, rodents, mediate uterine implantation, initiate the process of such as mouse and rat, also possess hemochorial placentation, and modulate vascular, endocrine and placenta (Rossant & Cross 2001, Soares et al. 2012). immunological properties to support successful preg- Placentation in both rodent and human is associated nancy. Improper trophectoderm (TE) specification results with the invasion of trophoblast cells into the uterine in either arrested preimplantation development or wall and remodeling of uterine spiral arteries with defective embryo implantation (Rossant & Cross 2001, invasive trophoblast cells. Despite several differences Cockburn & Rossant 2010, Roberts & Fisher 2011, Pfeffer between rodent and human placentation (Carter 2007), & Pearton 2012), which are the leading causes of early they share similar regulatory mechanisms controlling pregnancy failure. After embryo implantation, defective placental development (Rossant & Cross 2001, Pfeffer & development and function of trophoblast cells can lead Pearton 2012). Therefore, analyses of mutant mice to pregnancy failure and pregnancy-associated patho- provide opportunities to understand the functional logical conditions such as preeclampsia and intrauterine importance of transcription factors in trophoblast growth restriction (IUGR; Rossant & Cross 2001, development in hemochorial placentation. Successful Redman & Sargent 2005, Myatt 2006, Pfeffer & Pearton derivation of trophoblast stem cells (TSCs) from rodent 2012). Thus, a proper understanding of regulatory blastocysts (Tanaka et al. 1998, Asanoma et al. 2011) has mechanisms that control specification, differentiation also provided the excellent cell-based systems for and function of trophoblast cell types is critical for the biochemical analyses including mechanistic studies on advancement of infertility treatment and the improve- chromatin. The majority of the following discussion ment of reproductive health. However, our scope will be focused on our understanding from studies in for studying molecular mechanisms in the regulation of rodent models.

q 2014 Society for Reproduction and Fertility DOI: 10.1530/REP-14-0072 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 10/05/2021 08:14:52AM via free access R122 J G Knott and S Paul

Placental development and trophoblast cell types in Rossant & Cross 2001, Simmons & Cross 2005, Watson & rodents and human Cross 2005). In contrast, proliferation and differentiation of polar TE results in the formation of the ectoplacental cone Development of trophoblast cell lineage is a multi-step (EPC) and the chorion (Fig. 1B; Simmons & Cross 2005), process (Fig. 1). Specification of the TE, one of the first which arise during gastrulation (w7.0–7.25 dpc). The EPC two cell lineages within the preimplantation embryo is developed from polar TE-derived extra-embryonic (Kunath et al. 2004, Rossant 2004), initiates trophoblast ectoderm (ExE) and contributes to the formation of the development. The other earliest lineage is the inner cell junctional zone, a compact layer of cells sandwiched- mass (ICM), which contributes to the embryo proper. between the labyrinth zone and the maternal decidua Studies in rodent models indicate that TE cells, over- (Fig. 1C, a). Development of the labyrinth zone (Fig. 1C, a) laying the ICM (polar TE), contribute to the majority of starts with the attachment of the allantois to the chorion the trophoblast tissue and therefore are considered to be (Fig. 1B, b) at wE8.5 (Simmons & Cross 2005, Cross the TSC population (Rossant 2001). Establishment of et al. 2006). The chorion is a bilayered tissue with a layer bona fide TSC populations from rodent blastocysts of ExE-derived chorionic ectoderm (ChE), which (Tanaka et al. 1998, Asanoma et al.2011) further contains trophoblast stem/progenitor cells. Subsequent supports this concept. to chorio-allantoic attachment, differentiation and Rodent blastocysts implant to the uterus through mural morphogenesis of chorionic trophoblast progenitors and TE cells that are not in contact with the ICM (Fig. 1A). After establishment of vascular network from the allantoic implantation, cells of mural TE differentiate into post- mesoderm (Cross et al.2006) lead to the formation of mitotic primary trophoblast giant cells (primary TGCs; the labyrinth zone, which mediates nutrient exchange between the fetus and mother. Although the gross architecture of a rodent placenta A E3.5 has been known for many years, a more complete Polar TE Epiblast understanding of the hierarchy of the murine trophoblast Hypoblast Development of cell lineage has only been obtained recently (Uy et al. TE in the preimplantation 2002, Simmons et al. 2007, Mould et al. 2012, Ueno Mural embryo One-cell TE et al. 2013). Establishment of FGF4-dependent TSCs embryo Blastocyst from dissociated ExEs/EPCs and ChEs from postim- plantation mouse embryos (Tanaka et al. 1998, Uy B E7.5 E7.5 Primary et al. 2002) confirmed the presence of trophoblast cells EPC TGC EPC (contributes with TSC-potential within those tissues. However, to junctional zone) studies in mice predicted that a bonafide TSC population EPC cavity Development of trophoblast does not persist after the closure of EPC cavity (Uy et al. Chorion progenitors in Alantois extraembryonic tissues during 2002). Rather, recent studies (Simmons et al. 2007, (Contribute to gastrulation labyrinth Mould et al.2012, Ueno et al.2013)inmice zone) a Amnion b have suggested the presence of specific progenitor populations within the junctional and labyrinth zones C

Uterine spiral Invasive trophoblasts that could differentiate into specific specialized tropho- artery SpA-TGC Decidual blast cells of the mature placenta. cells Spiral Decidua artery Development of the junctional zone from the EPC is P-TGC associated with the derivation of multiple specialized Juctional zone Development of Arterial differentiated trophoblast cells, namely i) spongiotropblasts, ii) glyco- canal trophoblast Glycogen subtypes with gen cells and iii) secondary TGCs (Fig. 1C, b (top)). Based Spongiotrophoblasts cells specific C-TGC functions on the localization and gene expression patterns in the maturing Matemal placenta (Simmons et al. 2007, Hu & Cross 2010), three subtypes blood sinusoid of secondary TGCs were classified within the junctional

S-TGC zone and the decidua. These include the i) maternal SynTB-I arterial canal-associated TGCs (c-TGCs), ii) parietal- SynTB-II Fetal TGCs (p-TGCs) lining the implantation site, and iii) spiral a b vasculature artery-associated TGCs (SpA-TGC), which along with Figure 1 Different stages of mouse trophoblast development. (A) glycogen cells invade the decidua and therefore are Establishment of the TE in preimplantation embryo initiates trophoblast denoted invasive trophoblasts. Some of these invasive development. (B) Location of trophoblast progenitors in E7.5 mouse trophoblasts then associate with the uterine spiral arteries conceptus. (a) EPC in an E7.5 mouse embryo. (b) A cross section of an and remodel the arterial endothelium to establish E7.5 mouse embryo and a cartoon to indicate localization of primary TGCs and trophoblast progenitors. (C) Cartoons indicate different endovascular trophoblast population. Interestingly, line- regions of a mouse placenta (a) and differentiated trophoblast subtypes age-tracing studies indicated that these secondary TGCs and their localization at the maternal–fetal interface (b). could originate from different precursors. For example,

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PR domain zinc finger protein 1 (PRDM1)-positive A Floating villi Decidua proliferating cells within the spongiotrophoblasts are Uterus Uteroplacental implicated (Mould et al. 2012) as the precursors for the artery Endovascular SpA-TGCs, whereas trophoblast-specific protein alpha trophoblast Fetus

(Tpbpa)-positive precursors within the EPC could give rise space Intervillous TB cell to all three TGC subtypes (Simmons et al. 2007, Hu & column Anchoring Cross 2010). villous Extravillous CTB In addition to the above three TGC subtypes, maternal Placenta blood sinusoids within the labyrinth zone of mouse Chorionic plate vCTB placenta contain the sinusoidal TGCs (s-TGCs; Fig. 1C, b SynTB (bottom); Simmons et al. 2007, Hu & Cross 2010). The two layers of syncytiotrophoblasts (SynTB-I and SynTB-II, Fig. 1C, b) are also established within the labyrinth B (Simmons et al. 2008). The s-TGCs and SynTB-I/SynTB-II SynTB establish the trophoblast compartment for nutrient exchange within the rodent placenta. Interestingly, a vCTB recent study (Ueno et al.2013) has implicated a vCTB population of Epcamhi proliferating progenitor cells as the precursors of all three trophoblast subtypes within the CDX2 labyrinth. Collectively, these studies indicate a hierarchy Figure 2 Trophoblast cells in a human placenta. (A) Cartoons show of trophoblast development in rodents in which trophoblast cells at the maternal–fetal interface of a developing human developmental stage-specific progenitors are derived placenta. Chorionic villi stem from the chorionic plate and contain two from bonafide TSC populations. These stage-specific layers of trophoblast cells, the inner proliferating vCTBs and the outer progenitors then differentiate into specialized trophoblast SynTBs. In anchoring villi, maternal–fetal junctions are developed via cells of a mature placenta. formation of cell columns. Extravillous CTBs are immerged from the distal part of the cell column and invade into the decidua. Later, in Although we have obtained a more detailed knowledge the second trimester, a population of extravillous CTBs invades the of trophoblast development in rodents, our understanding uterine artery to establish endovascular trophoblasts. (B) The micro- of early stages of human trophoblast development is graph shows two layers of trophoblasts (CTBs and SynTBs) of a extremely poor due to ethical and experimental first-trimester (9-week) human placenta. The mouse TSC-specific limitations. Human preimplantation embryos express marker CDX2 is expressed in some CTBs but not in SynTBs. several transcription factors that are associated with TE-development in rodents. However, a proliferating At the interface of the maternal–fetal junction, within TSC/trophoblast progenitor population from a human the anchoring villi, the vCTBs adopt a different blastocyst or early postimplantation human placenta differentiation fate to establish migratory extravillous could not be established. Rather, our current under- CTBs, which invade the maternal decidua (Fig. 2A). standing of trophoblast development in human came Subsequently, a subset of the extravillous CTBs invades largely from studying placental tissues obtained from the uterine blood vessels. These endovascular tropho- terminated or premature pregnancies (Maltepe et al. blast cells extensively remodel the vascular endothelium 2010). Studies using first trimester human placentae thereby establishing blood vessels with the lining of demonstrated that the development of proliferating maternal endothelium and fetal trophoblast cells. villous cytotrophoblast cells (vCTBs) within chorionic Invasion of extravillous CTBs into the decidua and villi (Fig. 2A and B) is one of the early steps of human establishment of endovascular trophoblast population trophoblast development. Chorionic villi stem from the ensure increasing supply of maternal blood to the chorionic plate. Several of those villi anchor (anchoring intervillous space and enhanced nutrient exchange villi) to the uterine decidua via formation of a cell column, through the SynTBs. Defective invasion and endovascu- which is derived from proliferating vCTBs (Fig. 2A). These larization is considered to be the one of the major anchoring villi thereby establish the maternal–fetal reasons for pregnancy-associated disorders such as junction of a human placenta. In addition to anchoring preeclampsia (Redman & Sargent 2005). villi, numerous floating villi are established (Fig. 2A). The Differentiation of proliferating trophoblast progenitors vCTBs adapt two distinct differentiation fates in floating in both rodents and humans leads to the formation and anchoring villi to establish a mature placenta. The of SynTBs and invasive trophoblast cells that establish outer layers of both floating and anchoring villi contain an efficient nutrient exchange interface to ensure fetal SynTBs (Fig. 2A and B), which are established from fusion development. In addition to establishment of vascular of cell cycle-arrested vCTBs that were detached from the connection and nutrient exchange, trophoblast cells core mesenchyme. Thus, unlike in rodent placenta, secrete hormones, cytokines and angiogenic factors that a single layer of SynTBs is in contact with maternal alter the maternal endocrine and immune system to blood in a human placenta. ensure successful progression of pregnancy. Defective www.reproduction-online.org Reproduction (2014) 148 R121–R136

Downloaded from Bioscientifica.com at 10/05/2021 08:14:52AM via free access R124 J G Knott and S Paul development and function of trophoblast cell types positions of the embryo. Subsequently, distinct may lead to a multitude of pregnancy-associated transcriptional programs are established in outside vs disorders including preeclampsia, IUGR, pre-term inside cells. The expression of TE-specific genes is birth, miscarriage, and infertility. induced in outside cells and is reduced in inside cells of late eight- to 16-cell stage embryos, indicating an onset of TE-specification at these developmental stages Transcription factors and trophoblast cell lineage (Kunath et al. 2004, Rossant 2004, Zernicka-Goetz development 2005, Zernicka-Goetz et al. 2009, Home et al. 2012). However, blastomeres at these developmental stages are Genetic and biochemical studies with rodent models still plastic and could contribute to both TE and ICM have shown that the intricate process of trophoblast cell lineages. The determination of the TE-lineage happens at linage development is regulated by specific transcription the blastocyst stage and is associated with the formation factors/cofactors, which modulate gene expression i) of the blastocoel cavity that separates the TE from the during TE-development from totipotent blastomeres in ICM lineage (Pfeffer & Pearton 2012). Thus, transcrip- the preimplantation embryo, ii) in trophoblast stem/pro- tional regulation of TE-development in preimplantation genitors cells after embryo implantation and at the onset embryos can be divided into two phases: i) specification of placentation and iii) during differentiation of tropho- phase (a nascent plastic stage when TE-specific transcri- blast progenitors to specialized trophoblast subtypes ptional program is being established within the outer in the developing/matured placenta. The next sections blastomeres) and ii) determination phase (when of this review will discuss transcription factors that functional specificity is established within the TE lineage regulate the individual steps of trophoblast development. allowing segregation from the ICM lineage) (Fig. 3). Studies with mutant mouse embryos and mouse TSCs Transcription factors regulating TE-development in implicated transcription factors, such as Caudal-type homeobox protein-2 (CDX2), GATA-binding protein 3 preimplantation embryo (GATA3), transcription factor AP2 g (TCFAP2C) and Single-cell transcriptome analyses (Burton et al. 2013, TEAD4, in regulating proper execution of specification Xue et al. 2013, Yan et al. 2013) confirmed that, during and determination phases during TE-development (Niwa mouse and human preimplantation development, a et al. 2005, Yagi et al. 2007, Nishioka et al. 2008, Home minor wave of zygotic transcription starts within the et al. 2009, Ralston et al. 2010, Choi et al. 2012). CDX2 one-cell stage embryo and a major wave of transcription was the first transcription factor specifically found to be starts in the blastomeres of two- to four-cell stage involved in TE-development. CDX2 is ubiquitously embryos. Despite this early induction of zygotic expressed at the eight-cell stage. However, during the transcription, blastomeres are totipotent at these deve- morula-to-blastocyst transition CDX2 becomes restricted lopmental stages (Tarkowski & Wroblewska 1967, to the outer TE lineage (Dietrich & Hiiragi 2007, Veiga et al. 1987). In mice, beginning at the late Zernicka-Goetz et al. 2009). Interestingly, lack of eight-cell stage, blastomeres are polarized (Johnson & CDX2 in mouse embryos does not prevent blastocyst Ziomek 1981) and allocated to inside and outside formation. The embryos lacking CDX2 fail to maintain

TEAD4

Totipotent

Zygotic Zygotic Zygotic gene gene gene activation activation activation

One-cell Two-cell Four-cell Early eight-cell CDX2 Figure 3 Transcription factors regulating TE-develop- TEAD4 GATA3 TEAD4 KLF5 TCFAP2C ment in mouse preimplantation embryo. Blastomeres TEAD4 TEAD4 KLF5 SOX2 ELF5 in early stage (two to eight cells) embryos are KLF5 KLF5 SOX2 TCFAP2C EOMES SOX2 SOX2 TCFAP2C CDX2 ETS2 considered to be totipotent. However, several TCFAP2C TCFAP2C GATA3 GATA3 OCT1? Specification Determination TE-specific factors including TEAD4 are induced Apical Nascent Outer Polar Epiblast during zygotic gene activation. Beginning late eight- pole ICM ICM cells TE cell stage, cells are located in an inside vs outside position instigating TE-specification, which continues Initiation Blastocoel Compaction Cavitation Blastocoel of Expansion until the TE-determination phase. The determination Inner cavitation Nascent cells Mural phase ensures the development of the functional TE TE Hypoblast Late Morula/early Early Late TE-lineage in a matured blastocyst. Transcription eight-cell Morula blastocyst blastocyst blastocyst factors that are considered to be important at different stages of TE-development are indicated on top.

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Downloaded from Bioscientifica.com at 10/05/2021 08:14:52AM via free access Regulators of trophoblast lineage in mammals R125 a blastocoel cavity and are unable to implant (Strumpf blastomeres, with outer blastomeres having nuclear YAP et al. 2005). Thus, CDX2 function seems to be essential and inner blastomeres lacking nuclear YAP. The model for the maintenance of a functional TE rather than proposed that altered nuclear localization of YAP specification of the TE-lineage from totipotent blasto- modulates TEAD4 transcriptional activity in outer vs meres. However, gain-of-function analyses in mouse inner blastomeres (Nishioka et al. 2009, Cockburn et al. embryonic stem cells (ESCs) showed that ectopic 2013, Hirate et al. 2013, Leung & Zernicka-Goetz 2013, induction of CDX2 alone could promote a TSC-like Lorthongpanich et al. 2013). However, comparative fate in ESCs, indicating that CDX2 function could analyses of endogenous TEAD4 expression in blastocysts contribute to the specification of the TE lineage and of multiple mammalian species indicated that cells of other factors might compensate the loss of CDX2 during the ICM lineage largely lack nuclear TEAD4, thereby specification of the TE-lineage (Nishiyama et al. 2009). compromising transcription of TEAD4 target genes Other transcription factors, such as GATA3, may (Home et al. 2012). In contrast, cells of the TE-lineage compensate for CDX2 during the development of the maintain nuclear TEAD4, thereby allowing chromatin trophoblast lineage (Ralston et al. 2010). The expression occupancy at target genes and regulating their transcrip- analyses of GATA3 in mouse embryos showed that both tion. Thus, an alternate hypothesis is proposed indicating GATA3 and CDX2 follow a similar expression pattern that subcellular localization pattern of TEAD4 itself during early mouse development (George et al. 1994, is important in specifying a TE-specific transcriptional Home et al. 2009, Ralston et al. 2010). RNAi-mediated program in preimplantation embryos (Home et al. 2012, knockdown of GATA3 expression in mouse preimplanta- Saha et al. 2012). Another recent study (Kaneko & tion embryos impairs a TE-specific transcriptional DePamphilis 2013) indicated that TEAD4 could alter program and partially inhibits the morula-to-blastocyst the mitochondrial function and regulate oxidative transition (Home et al. 2009). Furthermore, ectopic phosphorylation in preimplantation embryos. However, induction of GATA3 in mouse ESCs could promote a during preimplantation development, a major shift of trophoblast fate (Ralston et al. 2010). However, unlike energy metabolism from anaerobic to oxidative phos- CDX2, GATA3 induction in ESCs does not restrict them phorylation as well as mitochondrial maturation begins in a self-renewing TSC-like state, but rather promotes the at the blastocyst stage (Houghton et al. 1996, Leese continuation of trophoblast differentiation (Ralston et al. 2012), whereas energy metabolism in earlier stage 2010). Thus, GATA3 might function both during embryos is mostly anaerobic. Thus, the TEAD4-mediated TE-development and subsequent differentiation of other regulation of oxidative phosphorylation might be more trophoblast cell types. important during the TE-determination phase rather than In preimplantation mouse embryos, TEAD4, a the TE-specification phase. Given the essential role of member of the TEA domain-containing transcription TEAD4 in TE-development, further research is necessary factor family, regulates the transcription of both Cdx2 to make a definitive conclusion about the mode of and Gata3 by physically occupying their chromatin TEAD4 function. domains (Yagi et al. 2007, Nishioka et al. 2008, Ralston Along with TEAD4, other transcription factors such as et al. 2010, Home et al. 2012). Loss of TEAD4 in mouse TCFAP2C, KLF5 and SOX2 may function in TE-specifica- embryos prevents the establishment of a TE-specific tion and blastocyst formation. TCFAP2C was shown to transcriptional program as characterized by loss of other be important for blastocoel formation and establishment TE-specific factors such as CDX2 and GATA3 (Yag i et al. of the TE epithelium during mouse preimplantation 2007, Nishioka et al. 2008, Ralston et al. 2010). Hence, development (Choi et al. 2012). Interestingly, genome- TEAD4 is indicated as the upstream factor to initiate wide analyses revealed that a large number of genes in the expression of CDX2, GATA3 and other key factors TSCs could be the common targets for both TEAD4 and for TE-specification. Furthermore, conserved nature of TCFAP2C (Home et al. 2012). Thus, specification of the TEAD4 expression within mammalian TE-lineage TE-lineage might be coordinated by both TCFAP2C and (Home et al.2012) indicates that TEAD-mediated TEAD4. The cooperative interaction between TCFAP2C TE-specification might be a common event during and CDX2 has also been indicated to be important preimplantation development in several mammals. during TE-development (Kuckenberg et al. 2010). Alternative mechanisms were proposed on how Kruppel-like factor 5 (KLF5; Lin et al. 2010) and SRY- TEAD4 mediates its function during preimplantation box 2 (SOX2; Keramari et al. 2010) are also implicated lineage development. TEAD4 is expressed in early in TE-development. However, in contrast to TEAD4, totipotent blastomeres and is also expressed in the ICM TCFAP2C, CDX2 and GATA3, the transcription factors lineage of a blastocyst. Thus, it is intriguing to understand KLF5 and SOX2 are important for formation of both ICM how TEAD4 specifically establishes a TE-specific and TE lineages (Lin et al. 2010). Loss of Klf5 expression developmental mechanism. The initial model (Nishioka prevents mouse development beyond the blastocyst et al. 2009) of TEAD4 function indicates that the Hippo stage and defective TE function is implicated for this signaling pathway alternatively regulates the nuclear phenotype. However, Klf5 also regulates the expression access of YAP, a TEAD4 cofactor, between outer vs inner of key pluripotency factors such as Oct4 and Nanog in www.reproduction-online.org Reproduction (2014) 148 R121–R136

Downloaded from Bioscientifica.com at 10/05/2021 08:14:52AM via free access R126 J G Knott and S Paul the ICM lineage. Therefore, a cell autonomous function the expression of core TSC-specific transcription factors, of KLF5 is proposed to promote proper transcriptional such as CDX2, GATA3 and TCFAP2C. Although these program in both TE and ICM lineage cells (Lin et al. core factors are induced in early preimplantation 2010). Like KLF5, SOX2 also regulates transcriptional embryos, their expression is maintained within the ExE programs in both TE and ICM lineages (Keramari et al. and EPC (Auman et al. 2002, Strumpf et al. 2005, 2010, Adachi et al. 2013). It has been shown that Ralston et al.2010). It has also been shown that depletion of both maternal and zygotic SOX2 reduces disruption of ELF5, ETS2 and POU5F1 leads to loss of the expression of several TE-specific genes (Keramari these core factors (e.g. CDX2) within the developing et al. 2010), including TEAD4. Thus, similar to KLF5, a postimplantation embryo (Georgiades & Rossant 2006, cell autonomous function of SOX2 might be important Sebastiano et al. 2010). These findings indicate that to promote a transcriptional program at the onset of development, maintenance, expansion and function TE-specification (Fig. 3). of trophoblast stem/progenitor cells within the rodent postimplantation embryo are regulated by a transcrip- tional circuitry involving several transcription factors. Transcription factors involved in proliferation and Interestingly, similar to the trophoblast stem/progeni- tor cells of a developing rodent placenta, proliferating maintenance of trophoblast stem/progenitor vCTBs of first trimester human placenta express key cells after embryo implantation transcription factors such as CDX2 and EOMES (Fig. 2B; Another essential stage of trophoblast lineage develop- Hemberger et al. 2010). However, in vitro culture of ment is the maintenance and expansion of trophoblast isolated vCTBs leads to cell cycle arrest. Therefore, stem/progenitor cells in the early postimplantation mechanistic studies to address the role of specific embryo. In mice, eomesodermin (Eomes) expression is transcription factors in self-renewal or differentiation of detected in the TE of blastocysts (Strumpf et al. 2005)and human trophoblast progenitors could not be performed also within the trophoblast stem/progenitors of the ExE and using the primary vCTBs. Rather, a CDX2-expressing EPC. Although Eomes-null mouse embryos form blasto- progenitor population within the chorionic mesenchyme cysts and undergo implantation, they die at E6.0–E7.5 due of human placenta has been identified (Genbacev et al. to improper differentiation of TE and defective expansion 2011), which in selective culture conditions adopt cell of the ExE (Strumpf et al. 2005). Several other transcription fates similar to differentiated trophoblast populations factors have also been implicated in the regulation of of chorionic villi. Still, the true nature of human trophoblast development in early postimplantation trophoblast stem/progenitor cells is yet to be defined embryos. These include two E twenty-six (ETS)-domain- and a model system similar to rodent TSCs is yet to be containing transcription factors, E74-like factor 5 (ELF5) established. The lack of a proper model system has and ETS2. Both ELF5 (Donnison et al. 2005, Ng et al.2008) limited our understanding of transcriptional mechanisms and ETS2 (Georgiades & Rossant 2006) are expressed in that control proliferation and differentiation of human the trophoblast stem/progenitor cells within the ExE trophoblast progenitors. and are essential for their maintenance (Wen et al. 2007, Ng et al. 2008). ExE development is defective in both ELF5 and ETS2-null embryos, causing defective Transcription factors regulating development and reciprocal interactions of ExE with the embryonic function of differentiated trophoblast cells ectoderm leading to impaired gastrulation, embryo patterning, and embryonic death (Donnison et al.2005, In rodents, successful completion of placentation and Georgiades & Rossant 2006, Polydorou & Georgiades establishment of the maternal–fetal interface are associ- 2013). The maintenance and differentiation of trophoblast ated with the development of multiple specialized stem/progenitor cells within the ExE is also regulated by a trophoblast subtypes within the junctional and labyrinth transcription factor, POU class 5 homeobox 1 (POU5F1; zones. In humans, these processes involve the differen- Sebastiano et al.2010). POU5F1-null embryos fail to tiation of vCTBs to SynTBs and extravillous CTBs. In establish a normal maternal–embryonic interface due to contrast to the proliferating trophoblast stem/progenitor compromised ExE development and lack of EPC formation population, terminally differentiated trophoblast cell (Sebastiano et al. 2010). Furthermore, similar to ELF5 types exhibit cell cycle arrest, morphological alterations, and ETS2,lossofPOU5F1 leads to early gastrulation cell–cell fusion, and undergo cell migration to invade the defect (Sebastiano et al. 2010). maternal decidua. However, identification of specific The involvement of multiple transcription factors in progenitor populations within the mouse spongiotropho- early postimplantation trophoblast development raises blasts and labyrinth (Simmons et al. 2007, Mould et al. the question, ‘how does a specific factor contribute to 2012, Ueno et al. 2013) indicates that proliferating, the maintenance or expansion of trophoblast stem/pro- undifferentiated trophoblast cell populations are main- genitor cells within ExE and EPC lineages?’ One possible tained within a maturing rodent placenta. Whereas such explanation is that these factors coordinate to maintain a progenitor population is yet to be identified in maturing

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Downloaded from Bioscientifica.com at 10/05/2021 08:14:52AM via free access Regulators of trophoblast lineage in mammals R127 human placenta, the continuous growth of human proper vascular network. Evidence of this came from placenta during second and third trimesters and mice with mutations in the AP1 family of transcription expansion of chorionic villi imply the presence of factors and homeobox transcription factor Esx1. AP1 proliferating trophoblast populations throughout factors are dimeric complexes of Jun (c-Jun, JunB, and gestation. Thus, a fine balance between cell proliferation JunD) homodimers and Jun heterodimers with FOS and cellular differentiation is important during the (c-FOS, FOSB, FOSL1, and FOSL2). Studies in mutant development of differentiated trophoblast populations mouse models indicated that Fosl1 (Schreiber et al. within maturing/mature placenta, and understanding 2000)andJunB (Schorpp-Kistner et al. 1999) are crucial transcriptional mechanisms that control this balance for proper vascular development within the labyrinth is of major importance to understand trophoblast zone. Loss of these factors leads to embryonic death due development. to impaired vascularization in the placental labyrinth. Establishment of chorioallantoic placenta is one of the Studies with Esx1-mutant mice (Li & Behringer 1998) key steps for successful placentation (Simmons & Cross also provided evidence that trophoblast cells play an 2005, Cross et al. 2006) in rodents. During chorionic active role during vascular remodeling within the placenta development, the allantoic mesoderm attaches labyrinth zone. Esx1 is an imprinted gene and in a with the chorion and the chorion collapses onto the mouse labyrinth it is exclusively expressed in trophoblast ectoplacental plate. Subsequently, invasion of the population. However, Esx1-mutant mice show an IUGR- chorionic plate by the allantoic blood vessels and like phenotype (Li & Behringer 1998) primarily due to trophoblast syntialization establish the labyrinthine defective fetal vessel growth within the layrinth zone. layer (Simmons & Cross 2005, Cross et al. 2006, Collectively, studies from mutant mice demonstrated the Simmons et al. 2008). Analyses of mouse mutants have importance of individual transcription factors for proper shown that a number of transcription factors, such as trophoblast differentiation and vascularization within the distal-less homeobox 3 (Dlx3; Morasso et al. 1999), Ets2 labyrinth zone. repressor factor (Erf; Papadaki et al. 2007) and ovo-like 2 Specific transcription factors have also been implicated (Ovol2; Unezaki et al. 2007) are important for proper in the development and function of differentiated chorioallontic fusion and labyrinth formation. trophoblast subtypes of the junctional zone. For example, The importance of spatio-temoral regulation of tropho- heart and neural crest derivatives-expressed transcript 1 blast cell proliferation during rodent labyrinth formation (HAND1; Riley et al. 1998) and PRDM1 (Mould et al. is better understood from mouse models with mutations 2012) are expressed within the trophoblast progenitors of in transcription factor glial cell missing 1 (Gcm1), the EPC and are important for TGC development. nuclear hormone receptors, (Slc7a1 (Errb)) and tumor Whereas, achaete–scute complex homolog 2 (ASCL2) is suppressor retinoblastoma (Epha4 (Rb)). Both Gcm1 and essential for spongiotrophoblast development (Tanaka Slc7a1 are expressed within the trophoblast progenitors et al. 1997). of the chorionic plate. Analyses in mutant mice One important difference during early vs late stages (Anson-Cartwright et al. 2000) and in TSCs (Hughes of trophoblast development is exposure to altered et al. 2004) indicated that GCM1 is important to induce oxygen level. Trophoblast development in early post- cell cycle arrest and formation SynTBs from chorionic implantation embryos occurs in the presence of low trophoblast progenitors. In contrast, Slc7a1 is important oxygen, whereas the later phases of trophoblast develop- to maintain proliferating diploid trophoblast progenitors ment occur in the presence of increased levels of oxygen in a developing placenta (Luo et al. 1997). The Slc7a1–b (Rodesch et al. 1992, Genbacev et al. 1997, Adelman mutant mice die at midgestation (E9.5–E10.5) and the et al. 2000). The hypoxia inducible factors (HIFs) are extraembryonic tissues in the mutant embryos are essential for proper differentiation and function of characterized with depletion of diploid trophoblast cells trophoblast cells. HIFs are heterodimeric proteins and an increase in secondary TGCs. The interrelationship consisting of alpha (HIFa) and beta (ARNT) subunits. of Gcm1 and Slc7a1 function during labyrinth formation The loss of Arnt and Hif1a within the mouse placenta is further evident from studies with Erf-mutant mice impairs spongiotrophoblast and TGC differentiation (Papadaki et al. 2007), in which chorionic trophoblast (Cowden Dahl et al. 2005), indicating that HIF-signaling cells lack Gcm1 expression and maintain Slc7a1 is important to regulate cell fate decision during expression leading to impaired labyrinth formation. differentiation of trophoblast progenitors (Fryer & Simon Interestingly, in contrast to Slc7a1-mutant mice, Epha4- 2006). In addition to the defective trophoblast differen- mutant mice exhibit the presence of an excessive amount tiation, loss of HIF function alters placental ultrastructure of proliferating cells within the labyrinth and decreased and leads to defective vasculature at placentation sites syncytialization (Wu et al. 2003), reiterating the import- (Cowden Dahl et al. 2005). It has also been shown that ance of proper regulation of cell proliferation during HIFs regulate the expression of histone deacetylases trophoblast differentiation in the labyrinth zone. (HDACs) in TSCs, and crosstalk between the HIFs and During labyrinth formation, transcriptional the HDACs might balance proper TSC differentiation mechanisms are also important for the establishment of (Maltepe et al.2005). Thus, during placental www.reproduction-online.org Reproduction (2014) 148 R121–R136

Downloaded from Bioscientifica.com at 10/05/2021 08:14:52AM via free access R128 J G Knott and S Paul development, HIF-mediated transcriptional mechanisms 2009, Gasperowicz et al.2013) in trophoblast are important for a multitude of events including development and function. Table 1 summarizes several placental morphogenesis, vascular remodeling and transcription factors and cofactors that regulate the trophoblast fate adoption. development of specific trophoblast subtypes or their Polyploidy is another unique characteristic of the function. Many of the factors that are important for mouse differentiated TGC population, although the importance trophoblast development are conserved in human of endoreplication in TGCs is poorly understood. Never- trophoblast cells and mediate similar functions. For theless, recent studies with the atypical E2F family of example, GCM1 was shown to regulate the expression transcription factors, which regulate polyploidy, have of retroviral syncytin genes in human trophoblast cells to provided important insights during mouse placental promote syncytiotrophoblast formation (Yu et al. 2002, development. E2F family consists of canonical E2F Liang et al. 2010). Similarly, GATA factors, FOSL1 and activators (E2F1, E2F2, E2F3a and E2F3b) and E2F HIFs are implicated in regulating critical aspects of repressors (canonical (E2F4, E2F5 and E2F6) and atypical trophoblast differentiation and invasion in both human (E2F7 and E2F8)). Analyses of mouse mutants indicated and rodents (Cheng & Handwerger 2005, Kent et al. 2011, that atypical E2F7/E2F8 repressors are essential for proper Renaud et al. 2014). However, our understanding of the placental development and function (Ouseph et al. global transcriptional circuitry involving these transcrip- 2012). Combinatorial loss of E2f7 and E2f8 leads to a tion factors during trophoblast development is severely compromised placental development, which is incomplete. Future research is necessary to identify associated with altered proliferation and differentiation of common transcriptional pathways that regulate both multiple differentiated trophoblast subtypes, including rodent and human trophoblast differentiation. Such TGCs and spongiotrophoblasts. studies will be important to establish a better under- Studies in knockout mice have implicated other standing of the global transcriptional circuitry in tropho- transcription factors and cofactors such as Pparg, blast progenitors vs differentiated trophoblast cells. Gata2/Gata3, Cited1, Cited2 and Tle3 (Ma et al. 1997, This will serve as an important step to further comprehend Barak et al. 1999, Ma & Linzer 2000, Rodriguez et al. the interrelationship between trophoblast development 2004, Withington et al. 2006, Parast et al. 2009, Ray et al. and pregnancy-associated disorders.

Table 1 Key factors that are implicated in proper development and function of differentiated trophoblast cells via gene-knockout studies in mice. Factor/cofactor Family and mode of function Functional importance References ASCL2/MASH2 A basic helix–loop–helix (bHLH) TF, Important for spongiotrophoblast development Tanaka et al. (1997) activator of transcription BLIMP1/PRDM1 A zinc finger transcriptional repressor of Required for differentiation of endovascular Mould et al. (2012) transcription TGCs CITED1 An Asp/Glu-rich C-terminal (CITED) Proper development of the spongiotrophoblast Rodriguez et al. (2004) domain transcriptional coactivator layer CITED2 (CITED) domain transcriptional coactivator Proper development of spongiotrophoblast, Withington et al. (2006) TGCs and invasive trophoblasts DLX3 Homeodomain TF Labrynth formation, placental vascularization Morasso et al. (1999) E2F7/E2F8 Winged-helix, transcriptional repressor Proper development of spongiotrophoblast and Ouseph et al. (2012) of transcription TGC layer ERF Transcriptional repressor Chorioallantoic attachment and absence of Papadaki et al. (2007) labyrinth FRA1 AP-1 family member TF, activator of Essential for proper labyrinth formation and Schreiber et al. (2000) transcription placental vascularization GATA2/GATA3 GATA binding factors, activator and Proper function and hormone production in Ma et al. (1997) repressor of transcription TGCs, vascularization at placentation site GCM1 TF, with a gcm-motif, activator of Essential for labyrinth formation and syncytio- Anson-Cartwright et al. (2000) transcription trophoblast TLE3 Transcriptional corepressor Proper differentiation into secondary TGCs Gasperowicz et al. (2013) HAND1 bHLH TF, activator and repressor of Regulates TGC formation Cross et al. (1995) and Riley transcription et al. (1998) HIFs bHLH TFs, activator of transcription Proper development of multiple trophoblast Cowden Dahl et al. (2005) and subtypes, trophoblast invasion, placental Maltepe et al. (2005) vascularization I-mfa bHLH TF, transcriptional repressor TGC differentiation and survival Kraut et al. (1998) JunB AP-1 family member TF, activator of Essential for proper labyrinth formation and Schorpp-Kistner et al. (1999) transcription vascularization OVOL2 Zinc-finger TF, transcriptional activator Labrynth formation, placental vascularization Unezaki et al. (2007) and repressor PPARg Ligand-activated nuclear hormone Proper differentiation of progenitors and proper Barak et al. (1999) and Parast receptor, activator of transcription development of labyrinth and giant cell layer et al. (2009)

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Epigenetic regulation of gene expression during important for normal proliferation and differentiation of trophoblast development trophoblast cells within the developing placenta. Genetic inactivation of Dnmt1 and Dnmt3a/Dnmt3b in mouse The development of distinct cell types from progenitors placenta leads to defective chorioallantoic attachment is often modulated by epigenetic modifications that alter (Li et al. 1992, Okano et al. 1999). Loss of Dnmt3l in nucleoprotein structure. During cell-lineage commitment, mouse placenta also leads to defective chorioallantoic transcription factors promote the expression of certain attachment and prevents labyrinth formation (Bourc’his genes by recruiting specific epigenetic regulators at their et al. 2001, Arima et al.2006), and Dnmt3l-null chromatin domains. Alternatively, epigenetic regulators placentae exhibit an abnormal spongiotrophoblast layer might facilitate the recruitment of a transcription factor at a and higher levels of TGCs (Arima et al. 2006). Thus, fine- specific locus. Altered DNA methylation is an epigenetic tuning of DNA methylation at trophoblast chromatin is mode of regulating gene expression. Other epigenetic critical to regulate proper differentiation of the tropho- regulators include factors that modulate histone modifi- blast progenitor. cation patterns at chromatin domains, as well as chromatin Another unique feature in trophoblast cells is organizers and chromatin remodeling factors. The next incorporation of regulatory regions/genes of retroviral section will briefly describe these epigenetic modifications origin (Haig 2012, Chuong et al.2013). These retroviral in the context of trophoblast development. genes and elements are indicated to be crucial for placental evolution and function (Haig 2012, 2013, Chuong et al. 2013). For example, the expression of DNA methylation and trophoblast development syncytins, which are retroviral envelope proteins, is In mammals, DNA methylation is mediated by a group essential to promote fusion of mononuclear trophoblasts of enzymes called DNA methyltransferases (DNMTs). and formation of the syncytiotrophoblast layer of both Among DNMTs, DNMT1 methylates post-replication, human (Mi et al.2000, Frendo et al. 2003) and rodent hemi-methylated DNA strands to restore global DNA (Dupressoir et al.2009, 2011) placentas. Also, other genes methylation patterns. In contrast, DNMT3A and of retrotransposon origin such as Peg10 and Rtl1 are DNMT3B could mediate de novo methylation at CpG essential in mouse placental development (Ono et al. islands near the promoter region of a gene instigating 2006, Sekita et al. 2008). Intriguingly, these genes of transcriptional silencing. The de novo methylation by retroviral origin are specifically expressed within tropho- DNMT3A and DNMT3B is stimulated by their direct blast cells and are repressed in most embryonic tissues interaction with another structurally similar protein, (Ono et al. 2001, 2006, Sekita et al. 2008) and several other DNMT3L, which by itself lacks DNA methyltransferase genes use retroviral regulatory elements to produce activity (Hata et al. 2002). Analyses in mouse preimplan- placenta-specific transcripts (Chuong et al. 2013). The tation embryos indicated that the DNA methylation reason behind the trophoblast-specific expression of patterns vary between the ICM and the TE (Santos et al. retroviral genes is unknown. Probably, the global DNA- 2002). The ICM development is associated with de novo hypomethylation within trophoblast cells create a per- DNA methylation. In contrast, the TE lineage virtually missive epigenetic state for elevated transcription of these lacks the DNA methylation, indicating that the initial retroviral genes, thereby facilitating adaptation, evolution specification of the TE is not dependent upon DNA and function of mammalian placenta. methylation. Furthermore, preimplantation mouse development is not impaired in the absence of Dnmt1, Histone modifications and trophoblast development Dnmt3a and Dnmt3b (Sakaue et al. 2010). Thus, DNA methylation is not essential for TE-development. Rather, Along with DNA-methylation, post-translational modifi- inequality of DNA methylation has been shown to be a cations (PTMs) of histones have also been implicated in critical epigenetic mechanism to establish distinct orchestrating transcriptional program during trophoblast transcriptional programs in embryonic vs extraembryonic development (Table 2). Importance of histone PTM during tissues during early postimplantation development. For specification of TE lineage came from a study (Torres- example, loss of DNA methylation at key trophoblast Padilla et al. 2007) showing that alteration of histone H3 genes, such as Elf5, induces their transcription and arginine 26-methylation (H3R26me) is associated with TE maintains a TSC-specific transcriptional program within vs ICM commitment of a blastomere. The study showed extraembryonic tissues of an early postimplantation that overexpression of coactivator-associated arginine mouse embryo (Ng et al. 2008), whereas transcriptional methyltransferase 1 (CARM1), which induces higher silencing via DNA methylation prevents the activation of levels of H3R26me, facilitates up-regulation of NANOG trophoblast genes in embryonic tissues. and SOX2 gene expression and facilitates ICM fate in Throughout embryonic development, the global DNA a blastomere. These studies indicate that suppression of hypomethylation is maintained within all extraembryonic histone H3 arginine methylation could be important to lineages, including trophoblast cells (Chapman et al. promote the TE-specific transcriptional program 1984, Rossant et al. 1986). However, DNA methylation is in blastomeres. However, additional experimentation is www.reproduction-online.org Reproduction (2014) 148 R121–R136

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Table 2 Summary of histone modifying enzymes that are implicated in trophoblast development. Enzyme Function Loss of function phenotype References CARM1 Histone arginine methyltransferase Increase in H3R26 methylation, increased expression Torres-Padilla et al. (2007) (H3R26me) of Nanog and Sox2, altered cell-fate, propensity to contribute to ICM EED PRC2 core component Ectopic induction represses TE-specific regulators and Wang et al. (2002) and Saha inhibits implantation, null embryos die at midgestation et al. (2012) and show improper differentiation of TGCs ESET Histone lysine methyltransferase Peri-implantation lethality due to defective ICM Dodge et al. (2004), Yeap (H3K9me3) development et al. (2009) and Yuan et al. (2009) EZH2 A PRC2 core component, regulates Early embryonic lethality with impairment of both O’Carrol et al. (2001) H3K27 methylation embryonic and extra embryonic tissue development G9a Histone H3K9 methyltransferase Embryonic lethality with impaired chorioallantoic fusion Tachibana et al. (2002) KDM6B Histone H3K27 demethylase Delayed blastocyst maturation and loss of TE function Saha et al. (2012) resulting in defective embryo implantation LSD1 Histone H3K4 demethylase Impaired differentiation and migration of TSCs Zhu et al. (2014) MYST1/MYST2 Histone H3K14 acetyltransferase Lethality after embryo implantation, defective Thomas et al. (2008) and chorioallantoic attachment Kueh et al. (2011) SUV39H1 Histone lysine methyltransferase Loss of TE lineage plasticity due to altered H3K9Me3 Alder et al. (2010) and (H3K9me3) modification Rugg-Gunn et al. (2010) SUZ12 A PRC2 core component, regulates Early embryonic lethality with impairment of both Pasini et al. (2004) H3K27 methylation embryonic and extraembryonic tissue development necessary to establish a direct link between suppression repressor 2 (PRC2) complex. Recently, it has been of histone H3 arginine methylation and trophoblast reported that proper regulation of H3K27Me3 incorpor- development. Rather, histone arginine methylation is ation at TE-specific genes is important during preim- necessary for the maintenance of trophoblast progenitors plantation lineage development. Loss of H3K27Me3 in the postimplantation mouse embryo as gene knockout incorporation at the TE-specific genes such as Cdx2 and of histone arginine methyltransferase gene, Prmt1, Gata3 is essential for proper development of the TE impairs EPC formation in mice (Pawlak et al. 2000). lineage and embryo implantation (Saha et al. 2013). Histone H3 lysine 9 tri-methylation (H3K9Me3) is Analyses in mouse embryos indicated that coordinated another histone modification that is implicated in regulation of lysine-specific histone demethylase 6B and preimplantation mouse development. H3K9Me3 modifi- embryonic ectoderm development (EED), a core cation is regulated by multiple histone methyltransfer- component of PRC2, ensures the loss of He3K27Me3 ases, including ERG-associated protein with SET domain incorporation at the chromatin domains of TE/ (ESET). Genetic studies in mice showed that, in ICM- TSC-specific genes (Rugg-Gunn et al. 2010, Saha et al. lineage cells, ESET is essential to incorporate H3K9Me3 2013). Although loss of H3K27Me3 modification modification within the chromatin domains of key promotes TE-specific gene expression, incorporation of TE-specific genes, thereby suppressing their expression H3K27Me3 may be important for proper development and the induction of the TE-fate (Yeap et al. 2009, and differentiation of trophoblast progenitors. Analyses Yuan et al. 2009). In contrast, another histone H3K9 in mouse mutants revealed that loss of Eed leads to methyltransferase, suppressor of variegation 3–9 improper development of secondary TGCs (Wang et al. homolog 1 (SUV39H1), has been implicated to suppress 2002). Furthermore, loss of other Prc2 core components, ICM-specific genes within the TE-lineage cells (Alder enhancer of zeste homolog 2 (Ezh2) and suppressor of et al. 2010, Rugg-Gunn et al. 2010). Thus, specification zeste 12 (Suz12), leads to embryonic death at gastrula- of TE vs ICM lineage is critically dependent upon well- tion due to improper development of both embryonic regulated machinery, which ensures selective gene and extraembryonic tissues (O’Carroll et al. 2001, Pasini expression by regulating chromatin-domain specific et al. 2004). H3K9Me3 incorporation. Deletion of another H3K9 TE cells within preimplantation mouse embryos methyltransferase, G9a, in mouse embryo leads to are also enriched with histone H3/H4 acetylation and embryonic lethality with impaired chorioallantoic fusion histone H3 lysine 4-methylation (H3K4me; Sarmento (Tachibana et al.2002), indicating that chromatin et al. 2004, Gupta et al. 2008, Ma & Schultz 2008, domain-specific incorporation of the H3K9Me3 mark Wongtawan et al. 2011). A recent study has reported that is also important during later stages of trophoblast lysine-specific demethylase 1 (LSD1), which demethy- development. lates H3K4Me residue, regulates differentiation and H3K27Me3 is another histone modification migration of TSCs (Zhu et al. 2014). However, functional implicated in transcriptional repression of TE-specific importance of H3K4me or histone acetylation during genes within the ICM lineage cells (Saha et al. 2013). TE-development is yet to be established. Rather, mouse H3K27Me3 modification is regulated by polycomb embryos lacking histone H3K14 acetyltransferase,

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MYST1 and MYST2, show impaired development have begun to shed some light on the underlying role after implantation along with defective chorioallantoic of BRG1 in trophoblast development. For instance, fusion (Thomas et al. 2008, Kueh et al. 2011), indicating chromatin immunoprecipitation on Chip (ChIP–Chip) that histone H3K14 acetylation could be an impor- and transcriptome analysis revealed that the pluripo- tant epigenetic modification to control trophoblast tency genes Oct4 and Nanog are bona fide targets of differentiation. BRG1 in mouse blastocysts (Kidder et al. 2009). Functional analysis further established that BRG1 cooperates with CDX2 to repress Oct4 in the trophoblast Chromatin remodeling factors and trophoblast lineage (Wang et al. 2010). Moreover, studies in Cdx2- development inducible ESCs revealed that Oct4 and Nanog silencing Analyses in mutant mouse embryos revealed that is tightly associated with chromatin remodeling at key a subset of chromatin remodeling and/or chromatin regulatory regions (Carey et al. 2014), suggesting that organizer proteins is important for early trophoblast BRG1-dependent chromatin remodeling activity is development. These include the SWI/SNF family of necessary for pluripotency gene silencing. Besides its chromatin remodeling proteins, chromatin organizers repressive role in trophoblast development, BRG1 can such as SATB1 and SATB2, and an ortholog of the also cooperate with EOMES and TCFAP2C to positively Drosophila nucleosome remodeling factor NURF301. regulate Eomes, Elf5 and Cdx2 expression in undiffer- This section of the review will discuss our current entiated TSCs (Kidder & Palmer 2010). Ablation of knowledge on the biological role of chromatin remodel- BRG1, EOMES and TCFAP2C resultedinlossof ing proteins in trophoblast development. self-renewal and trophoblast differentiation. Altogether, Functional studies in mice have established an these studies highlight a dual role for BRG1 in negatively important role for the SWI/SNF proteins BRG1, BAF47 regulating ESC genes and positively controlling TSC and BAF155 in trophoblast development (Fig. 4). genes via interactions with distinct transcription factors Genetic ablation of Brg1, Baf47 and Baf155 results in in the trophoblast lineage. developmental arrest around the blastocyst stage and Other putative chromatin regulators have also been failure to implant in utero (Bultman et al. 2000, Guidi implicated in trophoblast self-renewal. For example, the et al. 2001, Kim et al. 2001). Closer examination of chromatin organizers SATB homeobox 1 (SATB1) and mutant blastocysts in vitro revealed defects in hatching SATB2 have been shown to be essential for maintaining a and/or failure to form outgrowth assays indicative of an stem-cell identity within rat TSCs (Asanoma et al. 2012). abnormal trophoblast layer. Recent mechanistic studies Mechanistic analyses showed that loss of SATB proteins in TSCs resulted in reduced expression of Eomes and loss of TSC self-renewal. Along with TSC self-renewal, proper differentiation of the trophoblast lineage is imperative Repression Trophoblast specification for the development of a functional placenta. The Closed chromatin Activation bromodomain plant homeodomain transcription factor BAF Oct4, and Nanog (BPTF), an ortholog of the Drosophila nucleosome remodeling factor NURF301, is essential for trophoblast BRG1 differentiation in early postimplantation embryos (Goller Trophoblast self-renewal et al. 2008). BPTF-null embryos die before midgestation Open chromatin and are characterized with drastically reduced or absent Open chromatin BAF EPCs. Several transcription factors important for Cdx2, Eomes, and Eomes Elf5 SATB trophoblast differentiation, including Ascl2 and Hand1, BRG1 are downregulated in BPTF-null embryos, suggesting Trophoblast differentiation that BPTF may positively regulate the expression of core Open chromatin transcription factors necessary for differentiation and Mash2, formation of a mature placenta. Future mechanistic and BPTF Hand1 studies should reveal the precise role of SATB proteins and BPTF in maintenance and differentiation of tropho- Figure 4 Role of chromatin remodeling/organizer proteins in tropho- blast development. During trophoblast specification BRG1 and BAFs blasts in vivo. (BAF47 and BAF155) negatively regulate Oct4 and Nanog expression to promote trophoblast development. Alternatively, BRG1 can positively regulate the expression of Cdx2, Eomes and Elf5 to promote Discussion and future perspectives trophoblast self-renewal. The chromatin organizer SATB1/2 can also The development of trophoblast lineage in a mammalian facilitate self-renewal by positively regulating Eomes expression in species is a multistage process, and unique as well trophoblasts. During trophoblast differentiation the chromatin remo- deling factor BPTF is necessary for transcriptional activation of Mash2 as overlapping transcriptional mechanisms are involved and Hand1. All three groups of proteins have established roles in in regulating those multiple developmental stages. inducing open and closed chromatin at target genes. Defining these transcriptional mechanisms is important www.reproduction-online.org Reproduction (2014) 148 R121–R136

Downloaded from Bioscientifica.com at 10/05/2021 08:14:52AM via free access R132 J G Knott and S Paul to better understand physiological processes that occur as Hippo signaling pathway) in TE-specification. at the maternal–fetal interface. A better understanding of However, their relevance in postimplantation maternal–fetal interaction is necessary for success in trophoblast development needs to be addressed. assisted reproduction and to address therapeutic strategies Also, other transcription factors (CDX2, GATA3 for various pregnancy-associated complications such as and TCFAP2C) are implicated in both preimplanta- IUGR, preeclampsia and pre-term birth. Stage-specific tion TE-development as well as postimplantation regulation of transcriptional mechanisms in trophoblast maintenance of trophoblast progenitors. However, cells are often regulated by cellular signaling pathways the precise functions of these factors or their target that are instigated by growth factors, cytokines and genes at distinct stages of trophoblast development reproductive hormones. Also, from an evolutionary are yet to be identified. perspective, the placenta is a highly active organ, and ii) Multiple signaling pathways are implicated in TSC placental structure and mode of function varies tremen- maintenance, trophoblast differentiation, invasion dously among different mammalian species. A major and endovascularization (Simmons & Cross 2005, driving force behind this variation is the adaptation of a Knofler 2010, Soares et al. 2012). However, how species to the environment. Along with intrinsic signaling these signaling pathways alter transcriptional mechanisms, environmental factors might modulate mechanisms to establish cell type-specific gene transcriptional mechanisms during trophoblast develop- expression programs are poorly understood. ment. As discussed earlier, a number of recent studies have iii) Most of the genetic studies related to transcrip- enriched our understanding about transcriptional tional mechanisms and trophoblast development mechanisms during trophoblast development. However, have been performed in mouse models. However, several limitations are also prominent. given the variation of trophoblast cells in different Probably, the most obvious limitation in our under- species, essentiality of those mechanisms might standing related to human trophoblast biology is absence vary from species to species. Thus, it is important of a proper cellular model to study regulatory mechanisms to distinguish common vs unique transcriptional (including transcriptional mechanisms) controlling estab- mechanisms of trophoblast development among lishment, maintenance, and differentiation of trophoblast multiple species. For example; a subset of progenitors. Although different alternative experimental chromatin remodeling/organizer proteins is critical approaches have been implemented to understand for trophoblast development in mice. Yet, it is still trophoblast development in human, the absence of a not known whether these proteins are required for proper cellular model system greatly limits our ability to trophoblast development in humans or associated conceptualize the importance of specific molecular with pregnancy complications such as first trime- mechanisms in pathological conditions, arising from ster miscarriages, preeclampsia, or IUGR. Studies defective trophoblast development. using human trophoblast tissues from abnormal Additional deficiencies in our understanding originate pregnancies will help answer these questions. from the differential placental ultra-structures as well as iv) Several of the pregnancy-associated complications different trophoblast populations among mammalian could be induced by environmental factors. species. For example, elegant studies have identified However, how does a specific environmental different specialized trophoblast populations including factor modulate transcriptional mechanisms in different subtypes of TGCs in mice. Also, specific trophoblast cells remains poorly understood. progenitor populations, from which these specialized trophoblast populations are derived, have also been Future studies in these contexts utilizing recent identified. However, proper importance of these tropho- technologies such as single-cell transcriptome analyses, blast populations in relation to human trophoblast genome-wide identification of transcription factor development is hard to fathom due to significantly different targets, as well as gene editing tools will help to address placental ultrastructure, differential gestational time these fundamental mechanistic questions and to better period, and differences in the actual process of placental understand physiological processes for successful development. Nevertheless, similarities between invasive reproduction. TGCs and human extravillous CTBs, the common process of endovascular remodeling, trophoblast syncytialization, Declaration of interest nutrient exchange between mother and fetus, and in endocrine function and immuno-modulation during The authors declare that there is no conflict of interest that could rodent and human placentation provide solid platforms be perceived as prejudicing the impartiality of the review. to ask specific questions. For example: Funding i) several recent studies have identified new factors This research was supported by NIH grants GM095347 to J G (such as TEAD4) and signaling mechanisms (such Knott and HD062546, HL104322, and HL106311 to S Paul.

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