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1.
Nat Cell Biol ; 25(8): 1121-1134, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37460697

RESUMO

The epigenetic mechanisms that maintain differentiated cell states remain incompletely understood. Here we employed histone mutants to uncover a crucial role for H3K36 methylation in the maintenance of cell identities across diverse developmental contexts. Focusing on the experimental induction of pluripotency, we show that H3K36M-mediated depletion of H3K36 methylation endows fibroblasts with a plastic state poised to acquire pluripotency in nearly all cells. At a cellular level, H3K36M facilitates epithelial plasticity by rendering fibroblasts insensitive to TGFß signals. At a molecular level, H3K36M enables the decommissioning of mesenchymal enhancers and the parallel activation of epithelial/stem cell enhancers. This enhancer rewiring is Tet dependent and redirects Sox2 from promiscuous somatic to pluripotency targets. Our findings reveal a previously unappreciated dual role for H3K36 methylation in the maintenance of cell identity by integrating a crucial developmental pathway into sustained expression of cell-type-specific programmes, and by opposing the expression of alternative lineage programmes through enhancer methylation.


Assuntos
Epigênese Genética , Histonas , Metilação , Histonas/genética , Histonas/metabolismo , Diferenciação Celular/genética , Fibroblastos/metabolismo , Linhagem da Célula/genética
2.
Nat Cell Biol ; 25(4): 579-591, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37024684

RESUMO

DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape's molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation.


Assuntos
Epigênese Genética , Epigenoma , Animais , Camundongos , Feminino , Gravidez , Epigenoma/genética , Placenta/metabolismo , Metilação de DNA , Proteínas do Grupo Polycomb/genética , DNA/metabolismo , Mamíferos/metabolismo
3.
Nat Struct Mol Biol ; 28(7): 594-603, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140676

RESUMO

DNA methylation plays a critical role during development, particularly in repressing retrotransposons. The mammalian methylation landscape is dependent on the combined activities of the canonical maintenance enzyme Dnmt1 and the de novo Dnmts, 3a and 3b. Here, we demonstrate that Dnmt1 displays de novo methylation activity in vitro and in vivo with specific retrotransposon targeting. We used whole-genome bisulfite and long-read Nanopore sequencing in genetically engineered methylation-depleted mouse embryonic stem cells to provide an in-depth assessment and quantification of this activity. Utilizing additional knockout lines and molecular characterization, we show that the de novo methylation activity of Dnmt1 depends on Uhrf1, and its genomic recruitment overlaps with regions that enrich for Uhrf1, Trim28 and H3K9 trimethylation. Our data demonstrate that Dnmt1 can catalyze DNA methylation in both a de novo and maintenance context, especially at retrotransposons, where this mechanism may provide additional stability for long-term repression and epigenetic propagation throughout development.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/genética , Elementos de DNA Transponíveis/genética , Desenvolvimento Embrionário/genética , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Células Cultivadas , Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Técnicas de Inativação de Genes , Genoma/genética , Histonas/metabolismo , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Proteína 28 com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Sequenciamento Completo do Genoma , DNA Metiltransferase 3B
4.
Cell Stem Cell ; 25(5): 622-638.e13, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31588046

RESUMO

Post-transcriptional mechanisms have the potential to influence complex changes in gene expression, yet their role in cell fate transitions remains largely unexplored. Here, we show that suppression of the RNA helicase DDX6 endows human and mouse primed embryonic stem cells (ESCs) with a differentiation-resistant, "hyper-pluripotent" state, which readily reprograms to a naive state resembling the preimplantation embryo. We further demonstrate that DDX6 plays a key role in adult progenitors where it controls the balance between self-renewal and differentiation in a context-dependent manner. Mechanistically, DDX6 mediates the translational suppression of target mRNAs in P-bodies. Upon loss of DDX6 activity, P-bodies dissolve and release mRNAs encoding fate-instructive transcription and chromatin factors that re-enter the ribosome pool. Increased translation of these targets impacts cell fate by rewiring the enhancer, heterochromatin, and DNA methylation landscapes of undifferentiated cell types. Collectively, our data establish a link between P-body homeostasis, chromatin organization, and stem cell potency.


Assuntos
Diferenciação Celular/genética , Plasticidade Celular/genética , RNA Helicases DEAD-box/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ribonucleoproteínas/metabolismo , Animais , Linhagem Celular , Montagem e Desmontagem da Cromatina/genética , RNA Helicases DEAD-box/genética , Metilação de DNA , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica/genética , Ontologia Genética , Homeostase/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/enzimologia , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Homeobox Nanog/metabolismo , Organoides/citologia , Organoides/diagnóstico por imagem , Organoides/metabolismo , Biossíntese de Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/metabolismo , RNA-Seq , Ribonucleoproteínas/genética , Ribossomos/metabolismo
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