E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

Abstract

In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development.

Multi- and Transgenerational Effects of Developmental Exposure to Environmental Levels of PFAS and PFAS Mixture in Zebrafish (Danio rerio)

“…In line with our null findings of changes in fecundity, WBP2NL expression was not associated with reproductive outcomes in a human study seeking prognostic fertilization factors [42]. Wbp2nl is silenced during early development [43]; thus, its activation in the F2 larvae by PFOS and the mixture may indicate aberrant epigenetic programming. While wbp2nl is mainly expressed by sperm, it is also found in the breast and kidney [44]-areas known to be PFAS targets [45,46].…”

Rif1 interacts with non-canonical polycomb repressive complex PRC1.6 to regulate mouse embryonic stem cells fate potential

“…The functional differences of the PRC1.6 complex resulted from these distinct recruitment mechanisms are of interest to be elaborated in the future. The PRC1.6 complex inhibits premature differentiation of mESCs by repressing germ cell-related genes (Dahlet et al 2021 ; Endoh et al 2017 ; Liu et al 2020 ; Maeda et al 2013 ; Mochizuki et al 2021 ; Suzuki et al 2016 ; Uranishi et al 2021 ), and loss of Max results in meiotic entry even in mESCs (Suzuki et al 2016 ). Similar to that of Pcgf6, we found downregulation of Rif1 also caused mis-regulation of genes in meiosis-related pathways (Fig.…”

“…Each contains a distinct Pcgf subunit (Gao et al 2012 ). The PRC1.6 complex, consisting of multiple subunits including Pcgf6, RNF2, RYBP, L3mbtl2, Mga, Max, and E2F6, is known to inhibit meiotic entry of embryonic cells by targeting meiosis and germline genes (Dahlet et al 2021 ; Endoh et al 2017 ; Liu et al 2020 ; Maeda et al 2013 ; Mochizuki et al 2021 ; Suzuki et al 2016 ; Uranishi et al 2021 ). Depletion of PRC1.6 subunits such as Pcgf6 or L3mbtl2 results in multiple defects in embryonic development, including failure of gastrulation, abnormal axis development, and embryonic lethality (Endoh et al 2017 ; Liu et al 2020 ; Qin et al 2012 ).…”

Intragenic CpG Islands and Their Impact on Gene Regulation

“…A more stable form of repression at CGIs is through DNA methylation. In somatic tissues, DNA methylation represses promoter CGIs at the inactivated X chromosome (Augui et al, 2011;Galupa and Heard, 2018), germline genes (Velasco et al, 2010;Dahlet et al, 2021;Mochizuki et al, 2021), imprinted genes (Barlow and Bartolomei, 2014), and some lineage-committed genes (Dahlet et al, 2020). Whilst H3K27me3 and DNA methylation are both repressive, they are typically mutually exclusive at CGIs (Brinkman et al, 2012;Statham et al, 2012).…”