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The Chd4 helicase regulates chromatin accessibility and gene expression critical for β-cell function in vivo
Diabetes ( IF 7.7 ) Pub Date : 2023-03-13 , DOI: 10.2337/db22-0939
Rebecca K Davidson 1, 2, 3 , Sukrati Kanojia 1, 2, 3 , Wenting Wu 2, 4 , Tatsuyoshi Kono 1, 2, 3 , Jerry Xu 2, 3, 5 , Meredith Osmulski 2, 3, 5 , Robert N Bone 2, 3 , Nolan Casey 2, 3 , Carmella Evans-Molina 1, 2, 3, 5, 6, 7, 8 , Emily K Sims 1, 2, 3, 5 , Jason M Spaeth 1, 2, 3, 5, 7
Affiliation  

The transcriptional activity of Pdx1 is modulated by a diverse array of coregulatory factors that govern chromatin accessibility, histone modifications, and nucleosome distribution. We previously identified the Chd4 subunit of the Nucleosome Remodeling and Deacetylase complex as a Pdx1- interacting factor. To identify how loss of Chd4 impacts glucose homeostasis and gene expression programs in β-cells in vivo, we generated an inducible-β-cell-specific Chd4 knockout mouse model. Removal of Chd4 from mature islet β-cells rendered mutant animals glucose intolerant, in part due to defects in insulin secretion. We observed an increased ratio of immature:mature insulin granules in Chd4-deficient β-cells that correlated with elevated levels of proinsulin both within isolated islets and from plasma following glucose stimulation in vivo. RNA- and ATACSequencing showed that lineage-labeled Chd4-deficient β-cells have alterations in chromatin accessibility and altered expression of genes critical for β-cell function, including MafA, Slc2a2, Chga, and Chgb. Knockdown of CHD4 from a human β-cell line revealed similar defects in insulin secretion and alterations in several β-cell-enriched gene targets. These results illustrate how critical Chd4 activities are in controlling genes essential for maintaining β-cell function. Article Highlights Pdx1:Chd4 interactions were previously shown to be compromised in β-cells from human donors with type 2 diabetes. β-cell-specific removal of Chd4 impairs insulin secretion and leads to glucose intolerance in mice. Expression of key β-cell functional genes and chromatin accessibility are compromised in Chd4-deficient β-cells. Chromatin remodeling activities enacted by Chd4 are essential for β-cell function under normal physiological conditions.

中文翻译:

Chd4 解旋酶调节染色质可及性和基因表达,这对体内 β 细胞功能至关重要

Pdx1 的转录活性受到多种共同调节因子的调节,这些因子控制染色质可及性、组蛋白修饰和核小体分布。我们之前将核小体重塑和脱乙酰酶复合物的 Chd4 亚基鉴定为 Pdx1 相互作用因子。为了确定 Chd4 的缺失如何影响体内 β 细胞的葡萄糖稳态和基因表达程序,我们构建了诱导型 β 细胞特异性 Chd4 敲除小鼠模型。从成熟的胰岛β细胞中去除Chd4会导致突变动物产生葡萄糖不耐受,部分原因是胰岛素分泌缺陷。我们观察到 Chd4 缺陷型 β 细胞中未成熟:成熟胰岛素颗粒的比例增加,这与体内葡萄糖刺激后孤立胰岛和血浆中胰岛素原水平的升高相关。RNA 和 ATACS 测序表明,谱系标记的 Chd4 缺陷型 β 细胞的染色质可及性发生了改变,并且对 β 细胞功能至关重要的基因表达也发生了改变,包括 MafA、Slc2a2、Chga 和 Chgb。从人类 β 细胞系中敲除 CHD4 揭示了胰岛素分泌的类似缺陷以及几个富含 β 细胞的基因靶标的改变。这些结果说明 Chd4 活性在控制维持 β 细胞功能所必需的基因方面有多么重要。文章要点 此​​前研究表明,患有 2 型糖尿病的人类捐赠者的 β 细胞中的 Pdx1:Chd4 相互作用受到损害。β 细胞特异性去除 Chd4 会损害胰岛素分泌并导致小鼠葡萄糖不耐受。Chd4 缺陷的 β 细胞中关键 β 细胞功能基因的表达和染色质可及性受到损害。Chd4 进行的染色质重塑活动对于正常生理条件下的 β 细胞功能至关重要。
更新日期:2023-03-13
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