Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte

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Title: Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte
Author(s): Hill, PWS
Leitch, HG
Requena, CE
Sun, Z
Amouroux, R
Roman-Trufero, M
Borkowska, M
Terragni, J
Vaisvila, R
Linnett, S
Bagci, H
Dharmalingham, G
Haberle, V
Lenhard, B
Zheng, Y
Pradhan, S
Hajkova, P
Item Type: Journal Article
Abstract: Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs)1. Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5–E11.52,3,4,5,6,7,8,9,10,11, including genome-wide loss of 5-methylcytosine2,3,4,5,7,8,9,10,11. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro12,13,14. Here we show, using an integrative approach, that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Our results also reveal an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will help to guide attempts to recapitulate complete gametogenesis in vitro.
Publication Date: 7-Mar-2018
Date of Acceptance: 1-Feb-2018
URI: http://hdl.handle.net/10044/1/57599
DOI: https://dx.doi.org/10.1038/nature25964
ISSN: 0028-0836
Publisher: Nature Publishing Group
Start Page: 392
End Page: 396
Journal / Book Title: Nature
Volume: 555
Sponsor/Funder: Commission of the European Communities
Commission of the European Communities
Commission of the European Communities
EMBO
Commission of the European Communities
Medical Research Council (MRC)
Wellcome Trust
Funder's Grant Number: 274206
242048
257082
EMBO YIP
648879
Peter Hill MRC Doctoral Prize
106954/Z/15/Z
Copyright Statement: © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
EMBRYONIC STEM-CELLS
PROMOTER DNA METHYLATION
GENOME-WIDE
TET PROTEINS
IN-VITRO
5-HYDROXYMETHYLCYTOSINE
DYNAMICS
DIFFERENTIATION
DEMETHYLATION
CHROMATIN
MD Multidisciplinary
General Science & Technology
Publication Status: Published
Online Publication Date: 2018-03-07
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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