RESUMO
Pioneer factors are a subclass of transcription factors that can bind and initiate opening of silent chromatin regions. Pioneer factors subsequently regulate lineage-specific genes and enhancers and, thus, activate the zygotic genome after fertilization, guide cell fate transitions during development, and promote various forms of human cancers. As such, pioneer factors are useful in directed cell reprogramming. In this review, we define the structural and functional characteristics of pioneer factors, how they bind and initiate opening of closed chromatin regions, and the consequences for chromatin dynamics and gene expression during cell differentiation. We also discuss emerging mechanisms that modulate pioneer factors during development.
Assuntos
Cromatina , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Diferenciação Celular/genética , Reprogramação Celular , ZigotoRESUMO
Enhancers are cis-regulatory elements that can stimulate gene expression from distance, and drive precise spatiotemporal gene expression profiles during development. Functional enhancers display specific features including an open chromatin conformation, Histone H3 lysine 27 acetylation, Histone H3 lysine 4 mono-methylation enrichment, and enhancer RNAs production. These features are modified upon developmental cues which impacts their activity. In this review, we describe the current state of knowledge about enhancer functions and the diverse chromatin signatures found on enhancers. We also discuss the dynamic changes of enhancer chromatin signatures, and their impact on lineage specific gene expression profiles, during development or cellular differentiation.
Assuntos
Cromatina , Histonas , Cromatina/genética , Histonas/metabolismo , Lisina/metabolismo , Elementos Facilitadores Genéticos/genética , RNARESUMO
Gene silencing by heterochromatin plays a crucial role in cell identity. Here, we characterize the localization, the biogenesis, and the function of an atypical heterochromatin, which is simultaneously enriched in the typical H3K9me3 mark and in H3K36me3, a histone mark usually associated with gene expression. We identified thousands of dual regions in mouse embryonic stem (ES) cells that rely on the histone methyltransferases SET domain bifurcated 1 (SETDB1) and nuclear set domain (NSD)-containing proteins to generate H3K9me3 and H3K36me3, respectively. Upon SETDB1 removal, dual domains lose both marks, gain signatures of active enhancers, and come into contact with upregulated genes, suggesting that it might be an important pathway by which genes are controlled by heterochromatin. In differentiated tissues, a subset of these dual domains is destabilized and becomes enriched in active enhancer marks, providing a mechanistic insight into the involvement of heterochromatin in the maintenance of cell identity.
Assuntos
Montagem e Desmontagem da Cromatina , Metilação de DNA , Elementos Facilitadores Genéticos , Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Células-Tronco Embrionárias Murinas/enzimologia , Processamento de Proteína Pós-Traducional , Animais , Linhagem Celular , Sequenciamento de Cromatina por Imunoprecipitação , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Heterocromatina/genética , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Metilação , Camundongos , RNA-Seq , TranscriptomaRESUMO
Chromatin function in telomeres is poorly understood, but it is generally viewed as repressive. Yet, telomeric DNA sequences are transcribed into long non-coding RNAs named TElomere Repeat-containing RNA (TERRA). As TERRA molecules mostly localize at telomeres, major research efforts have been made to understand their functions, and how TERRA transcription is regulated and affects telomere structure. This review describes the current state of knowledge about the nature of chromatin at telomeres, its functions, and the relation between chromatin structure and TERRA.
Assuntos
Cromatina/metabolismo , RNA Longo não Codificante/genética , Telômero/genética , Cromatina/genética , Regulação da Expressão GênicaRESUMO
Alternative lengthening of telomeres, or ALT, is a recombination-based process that maintains telomeres to render some cancer cells immortal. The prevailing view is that ALT is inhibited by heterochromatin because heterochromatin prevents recombination. To test this model, we used telomere-specific quantitative proteomics on cells with heterochromatin deficiencies. In contrast to expectations, we found that ALT does not result from a lack of heterochromatin; rather, ALT is a consequence of heterochromatin formation at telomeres, which is seeded by the histone methyltransferase SETDB1. Heterochromatin stimulates transcriptional elongation at telomeres together with the recruitment of recombination factors, while disrupting heterochromatin had the opposite effect. Consistently, loss of SETDB1, disrupts telomeric heterochromatin and abrogates ALT. Thus, inhibiting telomeric heterochromatin formation in ALT cells might offer a new therapeutic approach to cancer treatment.
