Toggle Main Menu Toggle Search

Open Access padlockePrints

A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development

Lookup NU author(s): Dr Vasileios Floros, Professor Patrick Chinnery

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Resetting of the epigenome in human primordial germ cells (hPGCs) is critical for development. We show that the transcriptional program of hPGCs is distinct from that in mice, with co-expression of somatic specifiers and naive pluripotency genes TFCP2L1 and KLF4. This unique gene regulatory network, established by SOX17 and BLIMP1, drives comprehensive germline DNA demethylation by repressing DNA methylation pathways and activating TET-mediated hydroxymethylation. Base-resolution methylome analysis reveals progressive DNA demethylation to basal levels in week 5-7 in vivo hPGCs. Concurrently, hPGCs undergo chromatin reorganization, X reactivation, and imprint erasure. Despite global hypomethylation, evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated. Remarkably, some loci associated with metabolic and neurological disorders are also resistant to DNA demethylation, revealing potential for transgenerational epigenetic inheritance that may have phenotypic consequences. We provide comprehensive insight on early human germline transcriptional network and epigenetic reprogramming that subsequently impacts human development and disease.


Publication metadata

Author(s): Tang WWC, Dietmann S, Irie N, Leitch HG, Floros VI, Bradshaw CR, Hackett JA, Chinnery PF, Surani MA

Publication type: Article

Publication status: Published

Journal: Cell

Year: 2015

Volume: 161

Issue: 6

Pages: 1453–1467

Print publication date: 04/06/2015

Online publication date: 04/06/2015

Acceptance date: 14/04/2015

Date deposited: 26/06/2015

ISSN (print): 0092-8674

ISSN (electronic): 1097-4172

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.cell.2015.04.053

DOI: 10.1016/j.cell.2015.04.053

PubMed id: 26046444


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share