ZNF865 (BLST) Regulates Human Cell Senescence and DNA Damage
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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.
Summary
Degenerative disc disease (DDD) is a major contributor to chronic low back pain, a leading cause of disability globally 1–3 . Cellular senescence has emerged as a key driver of disc degeneration 4,5 , characterized by cell-cycle arrest and the secretion of pro-inflammatory and matrix-degrading factors collectively termed the senescence-associated secretory phenotype (SASP). While the pathological role of senescent cells in musculoskeletal aging is increasingly recognized 6–8 , the upstream molecular regulators remain poorly understood. Here we identify a previously uncharacterized zinc finger protein, ZNF865, as a novel regulator of senescence and genomic stability in human nucleus pulposus (NP) cells. CRISPRi-mediated downregulation of ZNF865 in healthy NP cells induced senescence, increased expression of p16 and p21, and led to increases in DNA damage. Conversely, upregulation of ZNF865 in degenerative NP cells restored proliferation, suppressed senescence markers, reduced DNA damage, significantly diminished SASP factor secretion and restored transcriptomic and epigenetic profiles to a healthy phenotype. This study represents the first functional characterization of ZNF865 and establishes it as an important regulator for senescence in disc cells. These findings highlight ZNF865 as a promising therapeutic target for mitigating senescence-driven pathologies in DDD and potentially other age-related disorders.
