RESUMO
Polycomb repressive complexes PRC1 and PRC2 regulate expression of genes involved in proliferation and development. In mouse early embryos, however, canonical PRC1 localizes to paternal pericentric heterochromatin (pat-PCH), where it represses transcription of major satellite repeats. In contrast, maternal PCH (mat-PCH) is enriched for H3 lysine 9 tri-methylation (H3K9me3) and Hp1ß. How PRC1 is targeted to pat-PCH, yet excluded from mat-PCH, has remained elusive. Here, we identify a PRC1 targeting mechanism that relies on Cbx2 and Hp1ß. Cbx2 directs catalytically active PRC1 to PCH via its chromodomain (CD(Cbx2)) and neighboring AT-hook (AT(Cbx2)) binding to H3K27me3 and AT-rich major satellites, respectively. CD(Cbx2) prevents AT(Cbx2) from interacting with DNA at PCH marked by H3K9me3 and Hp1ß. Loss-of-function studies show that Hp1ß and not H3K9me3 prevents PRC1 targeting to mat-PCH. Our findings indicate that CD(Cbx2) and AT(Cbx2) separated by a short linker function together to integrate H3K9me3/HP1 and H3K27me3 states.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Heterocromatina/metabolismo , Complexo Repressor Polycomb 1/genética , Zigoto/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Centrômero , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Embrião de Mamíferos , Feminino , Heterocromatina/química , Histonas/genética , Histonas/metabolismo , Padrões de Herança , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Complexo Repressor Polycomb 1/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Alinhamento de Sequência , Transdução de Sinais , Zigoto/crescimento & desenvolvimentoRESUMO
In mammals, totipotent embryos are formed by fusion of highly differentiated gametes. Acquisition of totipotency concurs with chromatin remodeling of parental genomes, changes in the maternal transcriptome and proteome, and zygotic genome activation (ZGA). The inefficiency of reprogramming somatic nuclei in reproductive cloning suggests that intergenerational inheritance of germline chromatin contributes to developmental proficiency after natural conception. Here we show that Ring1 and Rnf2, components of Polycomb-repressive complex 1 (PRC1), serve redundant transcriptional functions during oogenesis that are essential for proper ZGA, replication and cell cycle progression in early embryos, and development beyond the two-cell stage. Exchange of chromosomes between control and Ring1/Rnf2-deficient metaphase II oocytes reveal cytoplasmic and chromosome-based contributions by PRC1 to embryonic development. Our results strongly support a model in which Polycomb acts in the female germline to establish developmental competence for the following generation by silencing differentiation-inducing genes and defining appropriate chromatin states.