The Transcription Factor YY1 Is Essential for Normal DNA Repair and Cell Cycle in Human and Mouse β-Cells

Identifying the mechanisms behind the beta-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 RNA sequencing to identify genes/pathways regulated by insulin resistance in beta-cells. We demonstrate herein that islets from 4-week-old nonobese and nondiabetic 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 beta-cells from diabetic db/db mice, mice fed a high-fat diet (HFD), and individuals with T2D. Chromatin immunoprecipitation sequencing profiling in EndoC-beta H1 cells, a human pancreatic beta-cell line, indicated that YY1 binding regions regulate cell cycle control and DNA damage recognition and repair. We then generated mouse models with constitutive and inducible YY1 deficiency in beta-cells. YY1-deficient mice developed diabetes early in life due to beta-cell loss. beta-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 beta-cells impaired beta-cell function and induced DNA damage. In summary, we identified YY1 as a critical factor for beta-cell DNA repair and cell cycle progression.