E2f6 and Mga transcription factors link polycomb repressive complex PRC1.6 to methylation of CpG islands
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PROVIDER: PRJNA322164 | ENA |
REPOSITORIES: ENA
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Project description:Silencing of a subset of germline genes is dependent upon DNA methylation (DNAme) post-implantation. However, these genes are generally hypomethylated in the ICM, implicating alternative silencing pathways before implantation. Indeed, in embryonic stem cells (ESCs), an overlapping set of genes, including germline “genome-defence” (GGD) genes, are upregulated following deletion of the H3K9 methyltransferase SETDB1 or subunits of the non-canonical PRC1 complex PRC1.6. Here, we show that in pre-implantation embryos and naïve ESCs (nESCs), hypomethylated promoters of germline genes bound by the PRC1.6 DNA-binding subunits MGA/MAX/E2F6 are enriched for RING1B-dependent H2AK119ub1 and H3K9me3. Accordingly, silencing of these genes in nESCs shows a greater dependence on PRC1.6 than DNAme. In contrast, GGD genes are hypermethylated in epiblast-like cells and their silencing is dependent upon SETDB1, PRC1.6/RING1B and DNAme, with H3K9me3 and DNAme establishment dependent upon MGA binding. Thus, GGD genes are initially repressed by PRC1.6, with DNAme subsequently engaged in post-implantation embryos.
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Project description: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.
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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:Genomic occupancy of MYC and members of the PRC1.6 complex (MGA, E2F6, MAX, L3MBTL2) in MGA WT (Empty) and MGA depleted (sgMga) KrasG12D Trp53 -/- mouse lung cancer lines
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Project description:E2f6 and Mga transcription factors link polycomb repressive complex PRC1.6 to methylation of CpG islands [E2f6 knockout]
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Project description:E2f6 and Mga transcription factors link polycomb repressive complex PRC1.6 to methylation of CpG islands [Mga knockout]
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Project description:Polycomb-group complexes are evolutionarily conserved epigenetic machineries that regulate stem cell fate decisions/development and are also implicated in tumorigenesis mainly by histone modification. PRC1 complexes mediates ubiquitylation of histone H2A on lysine 119 and consists of PRC1.1 to PRC1.6 complexes. Here, we studied the functional roles of a PRC1.6 molecule L3MBTL2 in neuroblastoma (NB) cells. L3MBTL2 knockout- and knockdown-experiments elucidated that L3MBTL2 depletion suppressed NB cell proliferation according with cell cycle arrest and gamma-H2A up-regulation. L3MBTL2 knockout profoundly suppressed xenograft tumor formation. Transcriptome analysis detected the suppressed cell cycle-related pathways and the activated the differentiation-related pathways. The remarkable de-repressed genes by the L3MBTL2 knockout were BRME1 and NRIP3. ChIP experiments showed co-localization of the PRC1.6 components PCGF6/E2F6/L3MBTL2 and MYCN at the transcription start sites (TSS) of these genes. L3MBTL2 knockout reduced H2AK119ub marks at the TSS regions but PCGF6 binding was heterogeneously changed. This study clarified the significance of PRC1.6 molecule L3MBTL2 in NB cell homeostasis and the epigenetic mechanism of the L3MBTL2-mediated gene suppression in NB that regulates the PRC1.6 complex localization and H2AK119 mono-ubiquitination in a gene locus-specific manner.
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Project description:The transcriptional regulator Mga of Streptococcus pyogenes (the group A streptococcus, GAS) is known to directly activate several virulence genes important for colonization and immune evasion during exponential growth. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to the uptake and metabolism of sugars. Although the divergent M1 and M4 Mga profiles were similar in size and content, the M6 JRS4 strain was clearly distinct, even from other M6 strains. Real-time RT-PCR and northern blot analysis validated our microarray results and confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. A novel ORF (Spy2036) encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga or grm. Mga was shown to bind directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and is able to activate two divergently transcribed genes from a single site in a class II background. Both class and serotype specific Mga-regulated genes, such as speB, were apparent. In fact, Mga activated speB as long as it was expressed in the wild type strain, although direct binding of Mga to the PspeB promoter could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS. Keywords: Wild-type vs Mga-
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