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The Transcription Factor YY1 is Essential for Normal DNA Repair and Cell Cycle in Human and Mouse β-cells
Diabetes ( IF 7.7 ) Pub Date : 2022-05-20 , DOI: 10.2337/db21-0908
Flavia Letícia Martins Peçanha 1 , Rami Jaafar 2 , Joao Pedro Werneck-de-Castro 1, 3 , Charalampia-Christina Apostolopolou 2 , Anil Bhushan 2 , Ernesto Bernal-Mizrachi 1, 3
Affiliation  

Identifying the mechanisms behind the β-cell adaptation-to-failure is important to develop strategies to manage type 2 diabetes (T2D). Using db/db mice at early stages of the disease process, we took advantage of unbiased RNAseq to identify genes/pathways regulated by insulin resistance in β-cells. We demonstrate herein that islets from 4-week-old non-obese and non-diabetic leptin-receptor deficient db/db mice exhibited downregulation of several genes involved in cell-cycle regulation and DNA repair. We identified the transcription factor Yin Yang 1 (YY1) as a common gene between both pathways. The expression of YY1 and its targeted genes was decreased in the db/db islets. We confirmed the reduction in YY1 expression in β-cells from diabetic db/db mice, mice fed high fat diet (HFD) and individuals with T2D. ChIP-seq profiling in EndocBH1 cells, a human pancreatic β-cell line, indicated that YY1 binding regions regulate cell-cycle control, DNA damage recognition and repair. We then generated mouse models with constitutive and inducible YY1 deficiency in β-cells. YY1 deficient mice developed diabetes early in life due to β-cell loss. β-cells from these mice exhibited higher DNA damage, cell cycle arrest and cell death as well as decreased maturation markers. Tamoxifen-induced YY1 deficiency in mature β-cells impaired β-cell function and induced DNA damage. In summary, we identified YY1 as a critical factor for β-cell DNA repair and cell-cycle progression.

中文翻译:

转录因子 YY1 对于人类和小鼠 β 细胞的正常 DNA 修复和细胞周期至关重要

确定 β 细胞适应衰竭背后的机制对于制定治疗 2 型糖尿病 (T2D) 的策略非常重要。在疾病过程的早期阶段使用 db/db 小鼠,我们利用无偏 RNAseq 来识别 β 细胞中胰岛素抵抗调节的基因/通路。我们在此证明,来自 4 周龄非肥胖和非糖尿病瘦素受体缺陷 db/db 小鼠的胰岛表现出与细胞周期调节和 DNA 修复有关的几个基因的下调。我们将转录因子 Yin Yang 1 (YY1) 鉴定为两个途径之间的共同基因。YY1 及其靶基因的表达在 db/db 胰岛中降低。我们证实了糖尿病 db/db 小鼠、高脂饮食 (HFD) 小鼠和 T2D 个体的 β 细胞中 YY1 表达减少。EndocBH1 细胞(一种人胰腺 β 细胞系)中的 ChIP-seq 分析表明,YY1 结合区调节细胞周期控制、DNA 损伤识别和修复。然后,我们生成了 β 细胞中存在组成型和诱导型 YY1 缺陷的小鼠模型。YY1 缺陷小鼠由于 β 细胞损失而在生命早期患上糖尿病。这些小鼠的 β 细胞表现出更高的 DNA 损伤、细胞周期停滞和细胞死亡,以及成熟标记物的减少。他莫昔芬诱导的成熟 β 细胞中 YY1 缺陷会损害 β 细胞功能并诱导 DNA 损伤。总之,我们确定 YY1 是 β 细胞 DNA 修复和细胞周期进展的关键因子。
更新日期:2022-05-20
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