Lewis Christian, Levis Hunter, Holbrook Jonah, Polaski Jacob T, Jacobsen Timothy D, Gullbrand Sarah E, Diekman Brian, Iatridis James C, Gertz Jason, Lawrence Brandon, Bowles Robby D
University of Utah Department of Biomedical Engineering, Salt Lake City, UT.
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
bioRxiv. 2025 Jun 18:2025.06.13.659603. doi: 10.1101/2025.06.13.659603.
Senescence has been shown to contribute to the progression of aging related diseases including degenerative disc disease (DDD). However, the mechanisms regulating senescence in the intervertebral disc (IVD) and other tissues/diseases remain poorly understood. Recently, in a CRISPRa genome-wide screen, our lab identified a previously uncharacterized zinc finger protein, ZNF865 (BLST), that regulates a wide array of genes related to protein processing, cell senescence and DNA damage repair. Here, we demonstrate that ZNF865 expression is correlated with age and disease state in human patient IVD samples and mouse IVD. Utilizing CRISPR-guided gene modulation, we show that ZNF865 is necessary for healthy cell function and is a critical protein in regulating senescence and DNA damage in intervertebral disc cells, with implications for a wide range of tissues and organs. We also demonstrate that downregulation of ZNF865 induces senescence and upregulation mitigates senescence and DNA damage in human nucleus pulposus (NP) cells. Importantly, upregulation of ZNF865 shifts the chromatin landscape and gene expression profile of human degenerative NP cells towards a healthy cell phenotype. Collectively, our findings establish ZNF865 as a novel modulator of genome stability and senescence and as a potential therapeutic target for mediating senescence/DNA damage in senescence related diseases and disorders.
衰老已被证明会促进包括退行性椎间盘疾病（DDD）在内的与衰老相关疾病的进展。然而，调节椎间盘（IVD）及其他组织/疾病中衰老的机制仍知之甚少。最近，在一项CRISPRa全基因组筛选中，我们实验室鉴定出一种以前未被表征的锌指蛋白ZNF865（BLST），它调节一系列与蛋白质加工、细胞衰老和DNA损伤修复相关的基因。在这里，我们证明ZNF865的表达与人类患者IVD样本和小鼠IVD中的年龄和疾病状态相关。利用CRISPR引导的基因调控，我们表明ZNF865对健康细胞功能是必需的，并且是调节椎间盘细胞衰老和DNA损伤的关键蛋白，对广泛的组织和器官都有影响。我们还证明，ZNF865的下调会诱导人类髓核（NP）细胞衰老，而上调则会减轻衰老和DNA损伤。重要的是，ZNF865的上调使人类退行性NP细胞的染色质景观和基因表达谱向健康细胞表型转变。总的来说，我们的研究结果确立了ZNF865作为基因组稳定性和衰老的新型调节因子，以及作为介导衰老相关疾病和病症中衰老/DNA损伤的潜在治疗靶点。
