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

Identifying the mechanisms behind the b-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 b-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 b-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 b-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 b-cells. YY1 deficient mice developed diabetes early in life due to b-cell loss. b-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 b-cells impaired b-cell function and induced DNA damage. In summary, we identified YY1 as a critical factor for b-cell DNA repair and cell-cycle progression.