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

Abstract

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.

Clinical analysis of Gabriele‐de Vries caused by YY1 mutations and literature review

“…Approximately, 90% of patients have varying degrees of motor retardation and intellectual disability (Cherik et al, 2022). Animal experiments on mice showed that knockout of the YY1 gene at the early stage of cortical development increased the apoptosis rate of neuroepithelial cells (NECs) and neural precursor cells (NPCs) and led the cell to stay in the G1/S phase (Martins Peçanha et al, 2022), which led to neurodevelopmental defects by affecting the development of neurons. This is consistent with the case of motor retardation as the first manifestation.…”

A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury

“…YY1 has been implicated in DNA damage recognition in β-cells 16 . To investigate whether YY1 responds to DNA damage in renal cells, HK-2 cells were treated with etoposide, a classic inducer of DNA damage 17 .…”

YY1 mediated DCUN1D5 transcriptional activation promotes triple-negative breast cancer progression by targeting FN1/PI3K/AKT pathway

“…Yin Yang 1 (YY1) is a zinc finger DNA-binding protein and a member of the GLI-Krüppel family. Accumulating evidence have suggested that YY1 could participate in numerous biological functions, such as cell proliferation [35][36][37], apoptosis [38][39][40], epithelialmesenchymal transition (EMT) [41,42] and drug resistance [43][44][45]. For triple-negative breast cancer, YY1 has also been identified as a critical promoter for tumor proliferation and invasion [25,26].…”