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1.
Cell ; 186(26): 5826-5839.e18, 2023 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-38101409

RESUMO

Super-enhancers are compound regulatory elements that control expression of key cell identity genes. They recruit high levels of tissue-specific transcription factors and co-activators such as the Mediator complex and contact target gene promoters with high frequency. Most super-enhancers contain multiple constituent regulatory elements, but it is unclear whether these elements have distinct roles in activating target gene expression. Here, by rebuilding the endogenous multipartite α-globin super-enhancer, we show that it contains bioinformatically equivalent but functionally distinct element types: classical enhancers and facilitator elements. Facilitators have no intrinsic enhancer activity, yet in their absence, classical enhancers are unable to fully upregulate their target genes. Without facilitators, classical enhancers exhibit reduced Mediator recruitment, enhancer RNA transcription, and enhancer-promoter interactions. Facilitators are interchangeable but display functional hierarchy based on their position within a multipartite enhancer. Facilitators thus play an important role in potentiating the activity of classical enhancers and ensuring robust activation of target genes.


Assuntos
Regulação da Expressão Gênica , Super Intensificadores , Transcrição Gênica , alfa-Globinas , Elementos Facilitadores Genéticos , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismo , alfa-Globinas/genética
2.
Bioessays ; 45(10): e2300047, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37404089

RESUMO

Despite ever-increasing accumulation of genomic data, the fundamental question of how individual genes are switched on during development, lineage-specification and differentiation is not fully answered. It is widely accepted that this involves the interaction between at least three fundamental regulatory elements: enhancers, promoters and insulators. Enhancers contain transcription factor binding sites which are bound by transcription factors (TFs) and co-factors expressed during cell fate decisions and maintain imposed patterns of activation, at least in part, via their epigenetic modification. This information is transferred from enhancers to their cognate promoters often by coming into close physical proximity to form a 'transcriptional hub' containing a high concentration of TFs and co-factors. The mechanisms underlying these stages of transcriptional activation are not fully explained. This review focuses on how enhancers and promoters are activated during differentiation and how multiple enhancers work together to regulate gene expression. We illustrate the currently understood principles of how mammalian enhancers work and how they may be perturbed in enhanceropathies using expression of the α-globin gene cluster during erythropoiesis, as a model.


Assuntos
Elementos Facilitadores Genéticos , alfa-Globinas , Animais , Elementos Facilitadores Genéticos/genética , alfa-Globinas/genética , Fatores de Transcrição/metabolismo , Regiões Promotoras Genéticas/genética , Biologia , Mamíferos/genética
3.
Bioessays ; 44(12): e2200145, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36253122

RESUMO

Cis-regulatory elements govern gene expression programs to determine cell identity during development. Recently, the possibility that multiple enhancers are orchestrated in clusters of enhancers has been suggested. How these elements are arranged in the 3D space to control the activation of a specific promoter remains unclear. Our recent work revealed that the TGFß pathway drives the assembly of enhancer clusters and precise gene activation during neurogenesis. We discovered that the TGFß pathway coactivator JMJD3 was essential in maintaining these structures in the 3D space. To do that, JMJD3 required an intrinsically disordered region involved in forming phase-separated biomolecular condensates found in the enhancer clusters. Our data support the existence of a relationship between 3D-conformation of the chromatin, biomolecular condensates, and TGFß-driven response during mammalian neurogenesis. In this review, we discuss how signaling (TGFß), epigenetics (JMJD3), and biochemical properties (biomolecular condensates nucleation) are coordinated to modulate the genome structure to guarantee proper neural development. Moreover, we comment on the potential underlying mechanisms and implications of the enhancer-mediated regulation. Finally, we point out the knowledge gaps that still need to be addressed.


Assuntos
Elementos Facilitadores Genéticos , Fator de Crescimento Transformador beta , Animais , Elementos Facilitadores Genéticos/genética , Fator de Crescimento Transformador beta/genética , Condensados Biomoleculares , Cromatina/genética , Regiões Promotoras Genéticas/genética , Mamíferos/genética
4.
Cell Rep ; 34(5): 108703, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33535042

RESUMO

Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-ßH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence ß cell function.


Assuntos
Proteínas de Transporte/metabolismo , Cromatina/metabolismo , Células Secretoras de Insulina/metabolismo , Proteínas de Membrana/metabolismo , Fosfoproteínas/metabolismo , Humanos
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