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Coordination of Germ Layer Lineage Choice by TET1 During Primed Pluripotency

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Coordination of Germ Layer Lineage Choice by TET1 During Primed Pluripotency Downloaded from genesdev.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Coordination of germ layer lineage choice by TET1 during primed pluripotency Xinlong Luo,1 Bernard K. van der Veer,1 Lei Sun,1 Michela Bartoccetti,1 Matteo Boretto,2 Hugo Vankelecom,2 Rita Khoueiry,1,3 and Kian Peng Koh1 1Laboratory for Stem Cell and Developmental Epigenetics, 2Laboratory of Tissue Plasticity in Health and Disease, Department of Development and Regeneration, Katholieke Universiteit Leuven, 3000 Leuven, Belgium Gastrulation in the early postimplantation stage mammalian embryo begins when epiblast cells ingress to form the primitive streak or develop as the embryonic ectoderm. The DNA dioxygenase Tet1 is highly expressed in the epiblast and yet continues to regulate lineage specification during gastrulation when its expression is diminished. Here, we show how Tet1 plays a pivotal role upstream of germ layer lineage bifurcation. During the transition from naive pluripotency to lineage priming, a global reconfiguration redistributes Tet1 from Oct4-cobound promoters to distal regulatory elements at lineage differentiation genes, which are distinct from high-affinity sites engaged by Oct4. An altered chromatin landscape in Tet1-deficient primed epiblast-like cells is associated with enhanced Oct4 expression and binding to Nodal and Wnt target genes, resulting in collaborative signals that enhance mesendo- dermal and inhibit neuroectodermal gene expression during lineage segregation. A permissive role for Tet1 in neural fate induction involves Zic2-dependent engagement at neural target genes at lineage priming, is dependent on the signaling environment during gastrulation, and impacts neural tube closure after gastrulation. Our findings provide mechanistic information for epigenetic integration of pluripotency and signal-induced differentiation cues. [Keywords: epigenetics; pluripotency; developmental signaling; cell fate; germ layer segregation; chromatin accessibility] Supplemental material is available for this article. Received June 10, 2019; revised version accepted January 27, 2020. Embryonic development in mammals involves an early tence to differentiate in response to inductive signaling phase of gastrulation, when cell movements result in a cues at earlier stages of epiblast transitions (Smith 2017). massive reorganization of the embryo from a hollow The molecular mechanisms acting upstream of germ layer sphere of cells, or blastocyst, into a multilayered gastrula lineage decisions remain unclear. following implantation (Tam and Loebel 2007). The gas- The developmental progression of the epiblast through trula contains three germ layers known as ectoderm, me- lineage priming and germ layer fate allocation has been soderm, and endoderm that contain progenitors of all largely recapitulated in vitro using embryonic stem cell tissues in the adult body. In mice, the onset of gastrulation (ESC) cultures (Niwa 2010). Murine ESCs derived from occurs at embryonic day E6.5 with the appearance of a the preimplantation E3.5 blastocyst can be maintained primitive streak in the posterior region of the embryo, in a homogenous “ground state” with unrestricted “na- through which epiblast cells ingress by an epithelial- ive” pluripotency in chemically defined medium contain- mesenchymal transition to form progenitor cells of the ing leukemia inhibitory factor (LIF) and inhibitors of two mesoderm and definitive endoderm, also known as “mes- differentiation-inducing kinase pathways, commonly endoderm” (ME). Descendents of epiblast cells that do not known as 2iL (Ying et al. 2008). A 2-d differentiation pass through the primitive streak form the surface and protocol of 2iL-adapted ESCs to transient epiblast-like neural ectoderm (NE). These early lineages are specified cells (EpiLCs) in vitro captures the gastrulation-poised temporally and spatially through the coordinated activi- “primed” pluripotent state of the postimplantation epi- ties of various signaling pathways downstream from blast (Hayashi et al. 2011; Buecker et al. 2014). Earlier dif- wingless-related integrated site (Wnt), Nodal and bone ferentiation models utilizing murine ESCs relied on morphogenetic protein (BMP) family receptors (Robertson cellular aggregation in nonadherent conditions to form 2014; Muñoz-Descalzo et al. 2015; Zinski et al. 2018). embryoid bodies (EBs) containing germ layer progenitors However, recent studies suggest that cells acquire compe- © 2020 Luo et al. This article is distributed exclusively by Cold Spring 3Present address: Epigenetics Group, International Agency for Research on Harbor Laboratory Press for the first six months after the full-issue publi- Cancer, 69008 Lyon, France. cation date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After Corresponding author: [email protected] six months, it is available under a Creative Commons License (Attribu- Article published online ahead of print. Article and publication date are tion-NonCommercial 4.0 International), as described at http://creative- online at http://www.genesdev.org/cgi/doi/10.1101/gad.329474.119. commons.org/licenses/by-nc/4.0/. 598 GENES & DEVELOPMENT 34:598–618 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/20; www.genesdev.org Downloaded from genesdev.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Coordination of lineage choice by TET1 mimicking the gastrula (ten Berge et al. 2008). Under dif- sion of all three TET genes is low during gastrulation ferentiation-permissive conditions, a synergistic interde- (Khoueiry et al. 2017), suggesting that an epigenetic regu- pendency between canonical Wnt/β-catenin and Nodal latory mechanism allows TET1 to influence lineage segre- signaling pathways drives ME differentiation (Funa et al. gation even when expression is down-regulated. 2015; Wang et al. 2017). Further lineage specification de- Here, we ask how Tet1 controls developmental out- pends on modulation of collaborative signal inputs; strong comes by coordinating pluripotency and differentiation Nodal signals in EBs favor a definitive endoderm fate signals at entry points in the molecular circuitries of early while low levels or Wnt favor a mesoderm fate (Gadue embryonic lineage segregation. Our findings clarify how et al. 2006), in agreement with how graded Nodal morpho- Tet1 regulates the primed pluripotency epigenetic land- gen gradients in the primitive streak drive patterning of scape at the crossroads of ME and NE fate entry, providing definitive endoderm anteriorly and mesoderm posteriorly a cellular memory that regulates engagement of Oct4, in vivo (Vincent et al. 2003; Schier 2009; Robertson 2014). Wnt/β-catenin, and Nodal signaling effectors at develop- The use of cell culture mimics of early embryonic differ- mental loci during gastrulation. entiation has facilitated recent exploration of genomic regulatory mechanisms underlying early developmental cell state transitions. For example, the transitions from Results naive to primed pluripotency during conversion of 2iL Tet1 is repatterned to developmental fate loci during ESCs to EpiLCs have revealed global reorganization of pluripotency transition the master pluripotency transcription factor Oct4 at cell state-specific enhancer sites (Buecker et al. 2014). In hu- To examine whether Tet1 genomic occupancy changes man and murine ESCs, Oct4 co-occupies distal regulatory during the transition between naive and primed pluripo- elements with Smad2 and Smad3 (Smad2/3), closely relat- tency, we first performed Tet1 chromatin immunoprecip- ed downstream intracellular effectors of TGF-β/Activin/ itation sequencing (ChIP-seq) in ESCs cultured in 2iL Nodal receptors (Shi and Massagué 2003), to regulate tar- (naive state) and following in vitro conversion to EpiLCs get genes including Oct4 (also known as Pou5f1), Nodal, (primed state). Based on differential binding intensities and its antagonist, Lefty1 (Mullen et al. 2011), in an auto- determined from biological replicates (n = 2) of wild-type regulatory feedback loop. Upon exit from pluripotency, (WT) cells and normalized to Tet1-deficient (knockout Oct4 continues to determine germ layer fate selection [KO]) negative controls (Supplemental Fig. S1A), we by promoting ME and repressing NE fate (Thomson defined Tet1-bound peaks preferentially enriched in et al. 2011), through new cooperative interactions with 2iL-treated ESCs (ESC-specific, 1256) or EpiLCs (EpiLC- tissue-specific and signal-dependent factors at lineage- specific, 5557) and those where Tet1 binding did not priming genomic sites (Funa et al. 2015; Simandi et al. show significant differences between the two states (com- 2016). Collectively, these studies suggest that the capacity mon, 5741) (Fig. 1A; Supplemental Table S1). The sizable of transcription factors (TFs) to access enhancer sites to numbers of EpiLC-specific binding peaks suggest the pres- drive cell fate choice is highly context-dependent. The ence of de novo Tet1 binding, in line with detection of complex circuitry that decides which factor(s) dominates EpiLC-specific and Tet1-dependent differentially hydrox- in the process of ESC commitment to ME or NE fate, ymethylated regions previously observed during ESC-to- whether stochastic or predetermined by regulators acting EpiLC differentiation (Khoueiry et al. 2017). Moreover, upstream of lineage bifurcation, remains to be worked out even though Tet1 binding profiles were preferentially en- in further detail. riched at gene promoter
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