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

Title: A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development
Authors: Tang, WWC
Dietmann, S
Irie, N
Leitch, HG
Floros, VI
Bradshaw, CR
Hackett, JA
Chinnery, PF
Surani, MA
Item Type: Journal Article
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.
Issue Date: 4-Jun-2015
Date of Acceptance: 14-Apr-2015
URI: http://hdl.handle.net/10044/1/62086
DOI: https://dx.doi.org/10.1016/j.cell.2015.04.053
ISSN: 0092-8674
Publisher: CELL PRESS
Start Page: 1453
End Page: 1467
Journal / Book Title: CELL
Volume: 161
Issue: 6
Copyright Statement: © 2015 The Authors. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ).
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
DNA METHYLATION
EPIGENETIC INHERITANCE
TRANSCRIPTION FACTORS
CELL FATE
IN-VITRO
DYNAMICS
MICE
SPECIFICATION
MECHANISMS
ERASURE
Animals
DNA Methylation
Embryo, Mammalian
Epigenesis, Genetic
Female
Gene Expression Regulation, Developmental
Gene Regulatory Networks
Genome, Human
Germ Cells
Humans
Male
Mice
Promoter Regions, Genetic
Retroelements
Germ Cells
Animals
Humans
Mice
Retroelements
DNA Methylation
Epigenesis, Genetic
Gene Expression Regulation, Developmental
Genome, Human
Female
Male
Gene Regulatory Networks
Embryo, Mammalian
Promoter Regions, Genetic
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
DNA METHYLATION
EPIGENETIC INHERITANCE
TRANSCRIPTION FACTORS
CELL FATE
IN-VITRO
DYNAMICS
MICE
SPECIFICATION
MECHANISMS
ERASURE
06 Biological Sciences
11 Medical And Health Sciences
Developmental Biology
Publication Status: Published
Online Publication Date: 2015-06-04
Appears in Collections:Clinical Sciences
Imaging Sciences
Faculty of Medicine



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