A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development
Walfred W.C. Tang5, Sabine Dietmann5, Naoko Irie, Harry G. Leitch, Vasileios I. Floros, Charles R. Bradshaw, Jamie A. Hackett, Patrick F. Chinnery, M. Azim Surani correspondence email
Open access funded by Wellcome Trust
Accepted: April 14, 2015
Received in revised form: March 27, 2015
Received: January 28, 2015
• SOX17-BLIMP1 with TFCP2L1 and KLF4 constitute a unique hPGC transcriptome
• hPGC transcriptome drives extensive DNA demethylation and chromatin reorganization
• Evolutionarily young and hazardous retrotransposons remain partially methylated
• Some demethylation resistant loci are candidates for epigenetic inheritance
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.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Received: January 28, 2015; Received in revised form: March 27, 2015; Accepted: April 14, 2015;
© 2015 The Authors. Published by Elsevier Inc.
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