Vitamin D Switches BAF Complexes to Protect ß Cells.
Cell
; 173(5): 1135-1149.e15, 2018 05 17.
Article
em En
| MEDLINE
| ID: mdl-29754817
ABSTRACT
A primary cause of disease progression in type 2 diabetes (T2D) is ß cell dysfunction due to inflammatory stress and insulin resistance. However, preventing ß cell exhaustion under diabetic conditions is a major therapeutic challenge. Here, we identify the vitamin D receptor (VDR) as a key modulator of inflammation and ß cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs association to PBAF and BAF chromatin remodeling complexes, respectively. Mechanistically, ligand promotes VDR association with PBAF to effect genome-wide changes in chromatin accessibility and enhancer landscape, resulting in an anti-inflammatory response. Importantly, pharmacological inhibition of BRD9 promotes PBAF-VDR association to restore ß cell function and ameliorate hyperglycemia in murine T2D models. These studies reveal an unrecognized VDR-dependent transcriptional program underpinning ß cell survival and identifies the VDRPBAF/BAF association as a potential therapeutic target for T2D.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Vitamina D
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Proteínas Cromossômicas não Histona
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Receptores de Calcitriol
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Células Secretoras de Insulina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article