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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 vivo, 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 mammalian development.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Embryonic Stem Cell

SUBMITTER: Johana Chicher

LAB HEAD: Michael Weber

PROVIDER: PXD023974 | Pride | 2021-04-22

REPOSITORIES: Pride

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			Action	DRS
	2019_S48_JVallet_E2F6HA_IP1_14-10_dil3.mgf	Mgf
	2019_S48_JVallet_E2F6HA_IP1_14-10_dil3.raw	Raw
	2019_S48_JVallet_E2F6HA_IP1_18-07_dil5.mgf	Mgf
	2019_S48_JVallet_E2F6HA_IP1_18-07_dil5.raw	Raw
	2019_S48_JVallet_E2F6HA_IP1_8-10_dil3.mgf	Mgf

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Role of E2F6 in gene expression and DNA methylation during mouse development

Project description:In the mouse, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes in somatic cells, 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 vivo, a function that critically depends on the E2F6 marked box domain. Furthermore, inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Finally, we show that 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 mammalian development.

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Project description:In mammals, many germline genes are repressed by epigenetic mechanisms to prevent their illegitimate expression in embryonic and somatic cells. To advance our understanding of the complete mechanisms restricting the expression of germline genes in mammals, we analyzed the chromatin signature of germline genes and performed a genome-wide CRISPR-Cas9 knock-out screen for genes involved in germline gene repression using a reporter system in which GFP is under the control of the epigenetically repressed Dazl germline promoter in mouse embryonic stem cells (ESCs). We showed that the repression of germline genes mainly depends on the polycomb complex PRC1.6 and DNA methylation, which function additively in mouse ESCs. Furthermore, we identified and validated several novel genes involved in the repression of germline genes, and characterized three of them: Usp7, Shfm1 (also known as Sem1) and Erh. Inactivation of Usp7, Shfm1 or Erh led to the upregulation of germline genes, as well as retrotransposons for Shfm1, in mouse ESCs. Functionally, Usp7 acts at two levels: firstly it associates with PRC1.6 components and represses germline genes independently of DNA methylation, and secondly it facilitates DNA methylation deposition at germline genes for long term repression. In summary, our study provides a global view of the epigenetic mechanisms and novel factors required for silencing germline genes in embryonic cells.

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Project description:CpG island elements are associated with most mammalian gene promoters, yet how they contribute to gene regulation remains poorly understood. Recently it has become clear that a subset of CpG islands in embryonic stem cells can act as polycomb response elements and are recognized by the polycomb silencing systems to regulate the expression of genes involved in pluripotency and early developmental transcription programs. How CpG islands function mechanistically as nucleation sites for polycomb repressive complexes remains unknown. Here we discover that the KDM2B protein, by virtue of its ZF-CxxC DNA binding domain, specifically recognizes non-methylated DNA in CpG islands elements genome-wide. Through a physical interaction with the polycomb repressive complex 1 (PRC1), KDM2B targets PRC1 to CpG islands where it contributes to H2AK119ub1 and gene repression at a subset of polycomb targets. Unexpectedly, we also find that CpG islands are occupied by low levels of PRC1 throughout the genome, suggesting that the KDM2B-PRC1 complex may sample CpG island associated genes for susceptibility to polycomb mediated silencing. These observations demonstrate an unexpected and direct link between recognition of CpG islands by KDM2B and targeting of the polycomb repressive system. This provides the basis for a new model describing the functionality of CpG islands as mammalian PREs.

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CpG islands recruit a histone H3 lysine 36 demethylase [Agilent data]

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