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1.
Genes Dev ; 36(11-12): 699-717, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35710138

RESUMO

How distal regulatory elements control gene transcription and chromatin topology is not clearly defined, yet these processes are closely linked in lineage specification during development. Through allele-specific genome editing and chromatin interaction analyses of the Sox2 locus in mouse embryonic stem cells, we found a striking disconnection between transcriptional control and chromatin architecture. We traced nearly all Sox2 transcriptional activation to a small number of key transcription factor binding sites, whose deletions have no effect on promoter-enhancer interaction frequencies or topological domain organization. Local chromatin architecture maintenance, including at the topologically associating domain (TAD) boundary downstream from the Sox2 enhancer, is widely distributed over multiple transcription factor-bound regions and maintained in a CTCF-independent manner. Furthermore, partial disruption of promoter-enhancer interactions by ectopic chromatin loop formation has no effect on Sox2 transcription. These findings indicate that many transcription factors are involved in modulating chromatin architecture independently of CTCF.


Assuntos
Elementos Facilitadores Genéticos , Regiões Promotoras Genéticas , Fatores de Transcrição SOXB1/genética , Animais , Cromatina , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Fatores de Transcrição/metabolismo
2.
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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