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GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency

ABSTRACT: To elucidate the molecular basis of BMP4-induced differentiation of human pluripotent stem cells (PSCs) toward progeny with trophectoderm characteristics, we produced transcriptome, epigenome H3K4me3, H3K27me3, and CpG methylation maps of trophoblast progenitors, purified using the surface marker APA. We combined them with the temporally resolved transcriptome of the preprogenitor phase and of single APA+ cells. This revealed a circuit of bivalent TFAP2A, TFAP2C, GATA2, and GATA3 transcription factors, coined collectively the “trophectoderm four” (TEtra), which are also present in human trophectoderm in vivo. At the onset of differentiation, the TEtra factors occupy multiple sites in epigenetically inactive placental genes and in OCT4. Functional manipulation of GATA3 and TFAP2A indicated that they directly couple trophoblast-specific gene induction with suppression of pluripotency. In accordance, knocking down GATA3 in primate embryos resulted in a failure to form trophectoderm. The discovery of the TEtra circuit indicates how trophectoderm commitment is regulated in human embryogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE105022 | GEO | 2017/10/26

SECONDARY ACCESSION(S): PRJNA414434

REPOSITORIES: GEO

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Project description:The trophoblast cell lineage is specified as early as the blastocyst stage, leading to the individualization of trophectoderm from pluripotent cells of the inner cell mass. We used a double in vitro transcription mRNA amplification technique and compared trophectoderm with pluripotent stem cells. These five trophectoderm samples were compared to 176 human embryonic stem cell samples and adult samples that are publicly available in GEO under the following accession numbers: GSM136511 GSM136512 GSM136513 GSM136519 GSM136525 GSM136526 GSM172579 GSM175789 GSM175792 GSM175795 GSM175810 GSM175811 GSM175812 GSM175814 GSM175815 GSM175817 GSM175818 GSM175820 GSM175821 GSM175825 GSM175826 GSM175827 GSM175842 GSM175843 GSM175849 GSM175850 GSM175852 GSM175853 GSM175859 GSM175860 GSM175861 GSM175862 GSM175863 GSM175864 GSM175866 GSM175867 GSM175869 GSM175870 GSM175871 GSM175872 GSM175874 GSM175875 GSM175876 GSM175879 GSM175880 GSM175885 GSM175886 GSM175901 GSM175902 GSM175906 GSM175907 GSM175908 GSM175911 GSM175935 GSM175937 GSM175941 GSM175942 GSM175943 GSM175948 GSM175949 GSM175950 GSM175951 GSM175967 GSM175974 GSM175975 GSM175977 GSM175978 GSM175979 GSM175982 GSM175984 GSM175985 GSM175987 GSM175988 GSM175993 GSM175999 GSM176000 GSM176002 GSM176003 GSM176004 GSM176006 GSM176007 GSM176009 GSM176010 GSM176012 GSM176017 GSM176026 GSM176028 GSM176058 GSM176113 GSM176115 GSM176119 GSM176123 GSM176131 GSM176136 GSM176243 GSM176245 GSM176265 GSM176268 GSM176269 GSM176276 GSM176281 GSM176282 GSM176283 GSM176284 GSM176285 GSM176286 GSM176300 GSM176301 GSM176310 GSM176318 GSM176320 GSM176321 GSM176322 GSM176323 GSM176325 GSM176326 GSM176328 GSM176328 GSM176329 GSM176330 GSM176331 GSM176332 GSM176333 GSM176334 GSM176336 GSM176337 GSM176338 GSM176344 GSM176345 GSM176346 GSM176352 GSM176353 GSM176363 GSM176365 GSM176381 GSM176382 GSM176385 GSM176386 GSM176387 GSM176389 GSM176390 GSM176391 GSM176407 GSM176408 GSM176411 GSM176412 GSM176413 GSM176430 GSM176431 GSM176432 GSM176433 GSM176435 GSM183605 GSM183606 GSM183607 GSM183608 GSM183609 GSM194307 GSM194308 GSM245341 GSM248200 GSM248201 GSM248202 GSM248204 GSM249025 GSM249027 GSM257524 GSM288812 GSM288876 GSM288877 GSM388581 GSM388636 GSM388638 GSM452261 GSM452691 GSM453652

Project description:Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the “master regulator” of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.

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GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency

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