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 RNA sequencing to identify genes/pathways regulated by insulin resistance in β-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 β-cells from diabetic db/db mice, mice fed a high-fat diet (HFD), and individuals with T2D. Chromatin immunoprecipitation sequencing profiling in EndoC-βH1 cells, a human pancreatic β-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 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.

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F.L.M.P. and R.J. contributed equally.

See accompanying article, p. 1614.

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