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Transcriptome Analysis During Human Trophectoderm Specification Suggests New Roles of Metabolic and Epigenetic Genes

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Transcriptome Analysis During Human Trophectoderm Specification Suggests New Roles of Metabolic and Epigenetic Genes Transcriptome Analysis during Human Trophectoderm Specification Suggests New Roles of Metabolic and Epigenetic Genes Said Assou1,2., Ime`ne Boumela1,2., Delphine Haouzi1,Ce´cile Monzo1,2, Herve´ Dechaud1,2,3, Issac- Jacques Kadoch4, Samir Hamamah1,2,3* 1 CHU Montpellier, Institute for Research in Biotherapy, Hoˆpital Saint-Eloi, INSERM U1040, Montpellier, France, 2 Universite´ MONTPELLIER1, UFR de Me´decine, Montpellier, France, 3 ART-PGD department, CHU Montpellier, Hoˆpital Arnaud de Villeneuve, Montpellier, France, 4 De´partement d’Obste´trique Gyne´cologie, Universite´ de Montre´al, Hoˆpital Saint-Luc du CHUM, Montre´al, Canada Abstract In humans, successful pregnancy depends on a cascade of dynamic events during early embryonic development. Unfortunately, molecular data on these critical events is scarce. To improve our understanding of the molecular mechanisms that govern the specification/development of the trophoblast cell lineage, the transcriptome of human trophectoderm (TE) cells from day 5 blastocysts was compared to that of single day 3 embryos from our in vitro fertilization program by using Human Genome U133 Plus 2.0 microarrays. Some of the microarray data were validated by quantitative RT-PCR. The TE molecular signature included 2,196 transcripts, among which were genes already known to be TE-specific (GATA2, GATA3 and GCM1) but also genes involved in trophoblast invasion (MUC15), chromatin remodeling (specifically the DNA methyltransferase DNMT3L) and steroid metabolism (HSD3B1, HSD17B1 and FDX1). In day 3 human embryos 1,714 transcripts were specifically up-regulated. Besides stemness genes such as NANOG and DPPA2, this signature included genes belonging to the NLR family (NALP4, 5, 9, 11 and 13), Ret finger protein-like family (RFPL1, 2 and 3), Melanoma Antigen family (MAGEA1, 2, 3, 5, 6 and 12) and previously unreported transcripts, such as MBD3L2 and ZSCAN4. This study provides a comprehensive outlook of the genes that are expressed during the initial embryo-trophectoderm transition in humans. Further understanding of the biological functions of the key genes involved in steroidogenesis and epigenetic regulation of transcription that are up-regulated in TE cells may clarify their contribution to TE specification and might also provide new biomarkers for the selection of viable and competent blastocysts. Citation: Assou S, Boumela I, Haouzi D, Monzo C, Dechaud H, et al. (2012) Transcriptome Analysis during Human Trophectoderm Specification Suggests New Roles of Metabolic and Epigenetic Genes. PLoS ONE 7(6): e39306. doi:10.1371/journal.pone.0039306 Editor: Francisco Jose´ Esteban, University of Jae´n, Spain Received December 8, 2011; Accepted May 18, 2012; Published June 22, 2012 Copyright: ß 2012 Assou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Ferring and Genevrier pharmaceutical companies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Competing Interests: The authors have read the journal’s policy and have the following conflicts: This study was funded by Ferring and Genevrier pharmaceutical companies. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: [email protected] . These authors contributed equally to this work. Introduction cellular differentiation and transcriptional reprogramming. Al- though some genes that are specifically expressed in day 3 human Pre-implantation development of mammalian embryos encom- embryos and in TE cells, such as CCNA1 and GATA3 respectively passes a series of critical dynamic events, such as the transition have been identified [3,4], our knowledge on the changes in gene from a single-cell zygote to a multicellular blastocyst and the first expression associated with the initial embryo-TE transition and segregation of cells within the embryo with the formation of the the specification of the TE cell lineage is still limited. In addition, inner cell mass (ICM) surrounded by trophectoderm (TE) cells. since TE biopsies from day 5 human blastocysts might become a ICM retains pluripotency and gives rise to the embryo proper, reliable alternative to blastomere biopsies to assess the expression whereas TE cells play an important role in embryonic implanta- of biomarkers of embryo viability [5], a better knowledge of the tion in the uterine endometrium and placental formation. In genes that are specifically expressed in TE cells and the embryo humans, the embryonic genome activation (EGA) program is proper is crucial. Recent technological advances in mRNA functional by day 3 after fertilization [1]. The 6–8 cell stage amplification methods and DNA microarray assays have allowed embryo (day 3 post-fertilization) starts the process of ‘‘compaction’’ the simultaneous analysis of the transcript level of thousands of that leads to the generation of the tightly organized cell mass of the genes in one experiment, thus offering a global view of the morula and is followed by differentiation of the morula into a molecular events regulating physiological functions and cellular blastocyst [2]. The transition from day 3 embryos to day 5 processes [6,7]. Indeed, these methodologies have already blastocysts is likely to be controlled by many and specific changes contributed to improving our knowledge on the genetic network in the expression of different genes as this process involves both controlling key stages of pre-implantation embryo development PLoS ONE | www.plosone.org 1 June 2012 | Volume 7 | Issue 6 | e39306 Transcriptome Analysis of Embryo and Trophectoderm [8,9,10,11]. In this study, we used high-density oligonucleotide (PDK3) and Lactate Dehydrogenases (LDHC). The ‘‘TE molecular Affymetrix HG-U133P microarray chips to analyze the gene signature’’ comprised genes important for placental development transcription profiles of single day 3 human embryos and TE cells (PGF and TFAP2A), cytoskeleton-associated genes (Keratin 18 and isolated from day 5 blastocysts. By comparing the transcriptomes 19), and genes encoding S100 calcium binding proteins (S100P, of TE cells and day 3 embryos, we identified the specific molecular S100A6, 10, 13, 14 and 16), retinoid receptor-related testis- signature of human TE cells. These findings should provide a base associated receptors (NR2F2 and NR2F6) or the B receptor for investigating the molecular mechanisms of the embryo-TE (CCKBR). Moreover, genes encoding extracellular matrix proteins, transition as well as important insights for the development of such as Laminins (LAMA1, LAMA5 and LAMC1) and Integrins diagnostic tests to test blastocyst quality in assisted reproduction (ITGB4 and ITGB5) were also up-regulated. Gene ontology (GO) programs. annotations were used to explore the specific functional properties of the two molecular signatures (Figure 3). The day 3 embryo Results molecular signature was enriched in genes associated with localization in the ‘‘nucleus’’, while genes associated with the Dynamic Changes in Overall Gene Expression in Mature ‘‘cytoplasm’’ localization were over-represented in the TE MII Oocytes, Single Day 3 Embryos, TE Cells from Day 5 molecular signature. Concerning the ‘‘biological processes’’, the Blastocysts and hESCs day 3 embryo molecular signature was enriched in genes involved In order to determine the global gene expression variation in the in the regulation of cellular processes, transcription and post- different samples, we established the gene expression profile of translational protein modifications. Conversely, in the TE mature MII oocytes (n = 3), day 3 single embryos (n = 6), TE molecular signature, genes connected with different metabolic samples from day 5 blastocysts (n = 5) and hESCs (n = 4) (to and steroid biosynthetic processes were over-represented. The represent the ICM) by using high-density oligonucleotide Affyme- ‘‘molecular function’’ analysis showed that genes involved in trix HG-U133P microarray chips. A non-supervised analysis using oxido-reductase activity were significantly enriched in the TE the principal components analysis (PCA) showed that samples signature (p,0.001), whereas genes related to ‘‘GTPase activity’’ from the same group clustered together very tightly (Figure 1A), and DNA binding were over-represented in the day 3 embryo corroborating the robustness of the Affymetrix microarrays [12]. signature. Finally, the expression pattern of 11 genes belonging to Moreover, a non-supervised hierarchical clustering analysis of the the TE (GATA3, LAMA1, KRT18, HSD3B1, HSD17B1 and array data (based on 15,000 genes) clustered perfectly the different DNMT3L) or to the day 3 embryo molecular signature (MBD3L2, samples, confirming their very specific expression profiles CCNA1, BIK, RFPL2 and FIGLA) was confirmed by qRT-PCR (Figure 1B). Finally, a scatter plot analysis (Figure S1) showed analysis using specific primer pairs (Table S3). All qRT-PCR data that expression variations between mature MII oocytes and single were normalized to GAPDH to control for variations in mRNA day 3 embryos were high as illustrated by the dispersed scatter recovery and RT efficiency (Figure S2). plots and the low correlation coefficient (0.51). Conversely, the differences in gene expression between day 3 embryos and TE or Expression
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