@article{04c185965be54e9eab27d7169e19cc05,
title = "Sequential enhancer state remodelling defines human germline competence and specification",
abstract = "Germline-soma segregation is a fundamental event during mammalian embryonic development. Here we establish the epigenetic principles of human primordial germ cell (hPGC) development using in vivo hPGCs and stem cell models recapitulating gastrulation. We show that morphogen-induced remodelling of mesendoderm enhancers transiently confers the competence for hPGC fate, but further activation favours mesoderm and endoderm fates. Consistently, reducing the expression of the mesendodermal transcription factor OTX2 promotes the PGC fate. In hPGCs, SOX17 and TFAP2C initiate activation of enhancers to establish a core germline programme, including the transcriptional repressor PRDM1 and pluripotency factors POU5F1 and NANOG. We demonstrate that SOX17 enhancers are the critical components in the regulatory circuitry of germline competence. Furthermore, activation of upstream cis-regulatory elements by an optimized CRISPR activation system is sufficient for hPGC specification. We reveal an enhancer-linked germline transcription factor network that provides the basis for the evolutionary divergence of mammalian germlines.",
keywords = "Animals, Cell Differentiation/genetics, Embryonic Development/genetics, Endoderm, Gastrulation, Gene Expression Regulation, Developmental, Germ Cells/metabolism, Humans, Mammals",
author = "Tang, {Walfred W C} and Aracely Castillo-Venzor and Gruhn, {Wolfram H} and Toshihiro Kobayashi and Penfold, {Christopher A} and Morgan, {Michael D} and Dawei Sun and Naoko Irie and Surani, {M Azim}",
note = "Acknowledgements M.A.S. was supported by Wellcome Investigator Awards in Science (209475/Z/17/Z and 096738/Z/11/Z), an MRC research grant (RG85305) and a BBSRC research grant (G103986). W.W.C.T. received a Croucher Postdoctoral Research Fellowship and was supported by the Isaac Newton Trust. A.C.-V. was supported by the Wellcome 4-Year PhD Programme in Stem Cell Biology and Medicine and the Cambridge Commonwealth European and International Trust (203831/Z/16/Z). W.H.G. was supported by a BBSRC research grant (G103986). T.K. and M.A.S. were supported by Butterfield Awards of Great Britain Sasakawa Foundation. T.K. was supported by the Astellas Foundation for Research on Metabolic Disorders. D.S. was supported by a Wellcome Trust PhD studentship (109146/Z/15/Z) and the Department of Pathology, University of Cambridge. N.I. was supported by an MRC research grant (RG85305). We thank R. Barker and X. He for providing human embryonic tissues, and C. Bradshaw for bioinformatic support. We also thank The Weizmann Institute of Science for the WIS2 hESC line and the Genomics Core Facility of CRUK Cambridge Institute for sequencing services, and R. Alberio and members of the Surani lab for insightful comments and critical reading of the manuscript.",
year = "2022",
month = apr,
day = "11",
doi = "10.1038/s41556-022-00878-z",
language = "English",
volume = "24",
pages = "448--460",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "4",
}