A unique gene regulatory network resets the human germline epigenome for development
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Tang, W., Dietmann, S., Irie, N., Leitch, H., Floros, V., Bradshaw, C., Hackett, J., et al. (2015). A unique gene regulatory network resets the human germline epigenome for development. Cell, 161 1453-1467. https://doi.org/10.1016/j.cell.2015.04.053
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 naïve 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 on human development and disease.
W.C.C.T is supported by Croucher Foundation and Cambridge Trust. P.F.C.is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator with additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z). M.A.S. is supported by HFSP and Wellcome Trust Investigator Award.
WELLCOME TRUST (101876/Z/13/Z)
External DOI: https://doi.org/10.1016/j.cell.2015.04.053
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248261
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/