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

Abstract

SummaryResetting 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.

Transgenerational effects of childhood conditions on third generation health and education outcomes

“…Shortly after conception, when the first cell divisions are taking place, the stem cells are generally cleared of all methylation (Farooq, 2010, Mayer et al, 2000. However, recent evidence suggests that some loci associated with metabolic and neurological disorders are also resistant to DNA demethylation (Tang et al, 2015). If epigenetic modifications take place on the part of the genome that is genetically imprinted, this could explain sex-specific epigenetic inheritance.…”

Elucidating human male germ cell development by studying germ cell cancer

“…Here, the arriving PGCs not only maintain expression of the pluripotency genes, but also retain expression of SOX17, PRDM1 and PRMT5 (Eckert et al 2008). Recent data indicate that in humans, SOX17 is a critical determinant of PGC fate transactivating expression of PRDM1 (Irie et al 2015). In turn, PRDM1 and PRMT5 proteins cooperate to establish a symmetric dimethylation at arginine 3 of histones H2a and H4 (H2a/H4R3me2s), leading to suppression of somatic differentiation (Ohinata et al 2005, Ancelin et al 2006.…”

“…Further, PRDM14, which is essential for murine PGC maintenance, shows only low levels of expression in human PGC-like cells and seminomatous TCam-2 cells, which also share a similar gene expression profile with PGCs (Irie et al 2015, Nettersheim et al 2015, Sugawa et al 2015, Tang et al 2015.…”

“…However, two main differences have been reported so far. Using 'in vitro' differentiation protocols, SOX17 was identified as a key player of human PGC fate inducing PRDM1 expression and downstream GC genes (Irie et al 2015).…”

Mechanism and Reconstitution In Vitro of Germ Cell Development in Mammals

“…Recently, three groups independently reported genome-wide DNA methylation and transcription profiles of hPGCs obtained from aborted embryos at the stages of arrival of the hPGCs to-and proliferation/differentiation within-the genital ridges (corresponding to E9.5-E13.5 in mice) (Gkountela et al 2015;Guo et al 2015;Tang et al 2015), and revealed fundamental similarities in epigenome reprogramming between humans and mice. These discoveries have posed several critical challenges for the future.…”