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Dissecting the first transcriptional divergence during human embryonic development.

Bai Q, Assou S, Haouzi D, Ramirez JM, Monzo C, Becker F, Gerbal-Chaloin S, Hamamah S, De Vos J - Stem Cell Rev (2012)

Bottom Line: Several genes, including CCKBR and DNMT3L, were specifically up-regulated only in trophectoderm, indicating that the trophoblast cell lineage shares with the germinal lineage a transient burst of DNMT3L expression.A trophectoderm core transcriptional regulatory circuitry formed by 13 tightly interconnected transcription factors (CEBPA, GATA2, GATA3, GCM1, KLF5, MAFK, MSX2, MXD1, PPARD, PPARG, PPP1R13L, TFAP2C and TP63), was found to be induced in trophectoderm and maintained in placenta.The induction of this network could be recapitulated in an in vitro trophoblast differentiation model.

View Article: PubMed Central - PubMed

Affiliation: INSERM U1040, Montpellier, 34000, France.

ABSTRACT
The trophoblast cell lineage is specified early at the blastocyst stage, leading to the emergence of the trophectoderm and the pluripotent cells of the inner cell mass. Using a double mRNA amplification technique and a comparison with transcriptome data on pluripotent stem cells, placenta, germinal and adult tissues, we report here some essential molecular features of the human mural trophectoderm. In addition to genes known for their role in placenta (CGA, PGF, ALPPL2 and ABCG2), human trophectoderm also strongly expressed Laminins, such as LAMA1, and the GAGE Cancer/Testis genes. The very high level of ABCG2 expression in trophectoderm, 7.9-fold higher than in placenta, suggests a major role of this gene in shielding the very early embryo from xenobiotics. Several genes, including CCKBR and DNMT3L, were specifically up-regulated only in trophectoderm, indicating that the trophoblast cell lineage shares with the germinal lineage a transient burst of DNMT3L expression. A trophectoderm core transcriptional regulatory circuitry formed by 13 tightly interconnected transcription factors (CEBPA, GATA2, GATA3, GCM1, KLF5, MAFK, MSX2, MXD1, PPARD, PPARG, PPP1R13L, TFAP2C and TP63), was found to be induced in trophectoderm and maintained in placenta. The induction of this network could be recapitulated in an in vitro trophoblast differentiation model.

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Gene Ontology analysis of the TE and hESC signatures. a A Gene Ontology (GO) term enrichment analysis was carried out using FatiGO+. Only the GO terms that are significantly different (using adjusted p-values) between the two signatures are shown. A tag cloud shows the significant GO terms in each signature. The character size of each tag is proportional to their significance (see Materials and Methods). The details and the adjusted p-value of each term are shown in Supplementary Figure S2. b Heat map of the expression of all the extracellular matrix genes tagged by the GO term: 0031012 in the TE and hESC signatures showing the strong differential expression of extracellular matrix gene families in TE and hESC samples
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Fig3: Gene Ontology analysis of the TE and hESC signatures. a A Gene Ontology (GO) term enrichment analysis was carried out using FatiGO+. Only the GO terms that are significantly different (using adjusted p-values) between the two signatures are shown. A tag cloud shows the significant GO terms in each signature. The character size of each tag is proportional to their significance (see Materials and Methods). The details and the adjusted p-value of each term are shown in Supplementary Figure S2. b Heat map of the expression of all the extracellular matrix genes tagged by the GO term: 0031012 in the TE and hESC signatures showing the strong differential expression of extracellular matrix gene families in TE and hESC samples

Mentions: To further characterize the TE signature, we identified the gene ontology (GO) functional categories that are over- or under-represented in the TE signature. In comparison to the hESC signature, the TE signature was significantly enriched in genes implicated in cell protein synthesis, such as genes related to the categories ribosome (GO:0005840), structural constituent of ribosome (GO:0003735), biosynthetic process (GO:0009058), and translation (GO:0006412) (Fig. 3a and Supplementary Figure S2). The TE enrichment for genes involved in protein synthesis was remarkable and may in part be explained by CGA secretion as suggested by the high level of CGA mRNA. Conversely, the hESC signature was characterized by enrichment in genes involved in regulation of development and cell differentiation, such as anatomical structure development (GO:0048856), multicellular organismal development (GO:0007275) and cell adhesion (GO:0007155) (Fig. 3a and Supplementary Figure S2). Accordingly, in the hESC samples, developmental TFs, such as OTX2, HEY2, PBX1, were significantly up-regulated. The expression pattern of these TFs suggests that their expression in hESCs is not the manifestation of partial differentiation of such cells in culture, but rather an intrinsic property of these cells. Indeed, OTX2, a homeodomain-containing TF involved in brain and sensory organ development, and HEY2, a basic-loop-helix factor known to be involved in arterial-venous cell fate decision, are already expressed at the oocyte stage, before fertilization (see Supplementary Figure S5), suggesting a rapid and specific silencing in TE cells, whereas their expression is conserved in hESCs. Similarly, PBX1, a TF that control limb development from Drosophila to human, IRX1 and IRX3, two members of the Iroquois homeobox gene family, which play multiple roles during pattern formation of vertebrate embryos, were found expressed in many tissues but not in TE, suggesting a specific silencing in TE cells.Fig. 3


Dissecting the first transcriptional divergence during human embryonic development.

Bai Q, Assou S, Haouzi D, Ramirez JM, Monzo C, Becker F, Gerbal-Chaloin S, Hamamah S, De Vos J - Stem Cell Rev (2012)

Gene Ontology analysis of the TE and hESC signatures. a A Gene Ontology (GO) term enrichment analysis was carried out using FatiGO+. Only the GO terms that are significantly different (using adjusted p-values) between the two signatures are shown. A tag cloud shows the significant GO terms in each signature. The character size of each tag is proportional to their significance (see Materials and Methods). The details and the adjusted p-value of each term are shown in Supplementary Figure S2. b Heat map of the expression of all the extracellular matrix genes tagged by the GO term: 0031012 in the TE and hESC signatures showing the strong differential expression of extracellular matrix gene families in TE and hESC samples
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285757&req=5

Fig3: Gene Ontology analysis of the TE and hESC signatures. a A Gene Ontology (GO) term enrichment analysis was carried out using FatiGO+. Only the GO terms that are significantly different (using adjusted p-values) between the two signatures are shown. A tag cloud shows the significant GO terms in each signature. The character size of each tag is proportional to their significance (see Materials and Methods). The details and the adjusted p-value of each term are shown in Supplementary Figure S2. b Heat map of the expression of all the extracellular matrix genes tagged by the GO term: 0031012 in the TE and hESC signatures showing the strong differential expression of extracellular matrix gene families in TE and hESC samples
Mentions: To further characterize the TE signature, we identified the gene ontology (GO) functional categories that are over- or under-represented in the TE signature. In comparison to the hESC signature, the TE signature was significantly enriched in genes implicated in cell protein synthesis, such as genes related to the categories ribosome (GO:0005840), structural constituent of ribosome (GO:0003735), biosynthetic process (GO:0009058), and translation (GO:0006412) (Fig. 3a and Supplementary Figure S2). The TE enrichment for genes involved in protein synthesis was remarkable and may in part be explained by CGA secretion as suggested by the high level of CGA mRNA. Conversely, the hESC signature was characterized by enrichment in genes involved in regulation of development and cell differentiation, such as anatomical structure development (GO:0048856), multicellular organismal development (GO:0007275) and cell adhesion (GO:0007155) (Fig. 3a and Supplementary Figure S2). Accordingly, in the hESC samples, developmental TFs, such as OTX2, HEY2, PBX1, were significantly up-regulated. The expression pattern of these TFs suggests that their expression in hESCs is not the manifestation of partial differentiation of such cells in culture, but rather an intrinsic property of these cells. Indeed, OTX2, a homeodomain-containing TF involved in brain and sensory organ development, and HEY2, a basic-loop-helix factor known to be involved in arterial-venous cell fate decision, are already expressed at the oocyte stage, before fertilization (see Supplementary Figure S5), suggesting a rapid and specific silencing in TE cells, whereas their expression is conserved in hESCs. Similarly, PBX1, a TF that control limb development from Drosophila to human, IRX1 and IRX3, two members of the Iroquois homeobox gene family, which play multiple roles during pattern formation of vertebrate embryos, were found expressed in many tissues but not in TE, suggesting a specific silencing in TE cells.Fig. 3

Bottom Line: Several genes, including CCKBR and DNMT3L, were specifically up-regulated only in trophectoderm, indicating that the trophoblast cell lineage shares with the germinal lineage a transient burst of DNMT3L expression.A trophectoderm core transcriptional regulatory circuitry formed by 13 tightly interconnected transcription factors (CEBPA, GATA2, GATA3, GCM1, KLF5, MAFK, MSX2, MXD1, PPARD, PPARG, PPP1R13L, TFAP2C and TP63), was found to be induced in trophectoderm and maintained in placenta.The induction of this network could be recapitulated in an in vitro trophoblast differentiation model.

View Article: PubMed Central - PubMed

Affiliation: INSERM U1040, Montpellier, 34000, France.

ABSTRACT
The trophoblast cell lineage is specified early at the blastocyst stage, leading to the emergence of the trophectoderm and the pluripotent cells of the inner cell mass. Using a double mRNA amplification technique and a comparison with transcriptome data on pluripotent stem cells, placenta, germinal and adult tissues, we report here some essential molecular features of the human mural trophectoderm. In addition to genes known for their role in placenta (CGA, PGF, ALPPL2 and ABCG2), human trophectoderm also strongly expressed Laminins, such as LAMA1, and the GAGE Cancer/Testis genes. The very high level of ABCG2 expression in trophectoderm, 7.9-fold higher than in placenta, suggests a major role of this gene in shielding the very early embryo from xenobiotics. Several genes, including CCKBR and DNMT3L, were specifically up-regulated only in trophectoderm, indicating that the trophoblast cell lineage shares with the germinal lineage a transient burst of DNMT3L expression. A trophectoderm core transcriptional regulatory circuitry formed by 13 tightly interconnected transcription factors (CEBPA, GATA2, GATA3, GCM1, KLF5, MAFK, MSX2, MXD1, PPARD, PPARG, PPP1R13L, TFAP2C and TP63), was found to be induced in trophectoderm and maintained in placenta. The induction of this network could be recapitulated in an in vitro trophoblast differentiation model.

Show MeSH
Related in: MedlinePlus