Gürhan Gülben, Sevinç Kenan, Aztekin Can, Gayretli Mert, Yılmaz Alperen, Yıldız Abdullah Burak, Ervatan Elif Naz, Morova Tunç, Datlı Elif, Coleman Oliver D, Kawamura Akane, Lack Nathan A, Syed Hamzah, Önder Tamer
School of Medicine, Koç University, Istanbul, Turkey.
Vancouver Prostate Centre, Department of Urologic Science, University of British Columbia, Vancouver, BC, Canada.
Commun Biol. 2025 Mar 18;8(1):454. doi: 10.1038/s42003-025-07899-y.
Cell-autonomous barriers to reprogramming somatic cells into induced pluripotent stem cells (iPSCs) remain poorly understood. Using a focused CRISPR-Cas9 screen, we identified Ubiquitin-specific peptidase 22 (USP22) as a key chromatin-based barrier to human iPSC derivation. Suppression of USP22 significantly enhances reprogramming efficiency. Surprisingly, this effect is likely to be independent of USP22's deubiquitinase activity or its association with the SAGA complex, as shown through module-specific knockouts, and genetic rescue experiments. USP22 is not required for iPSC derivation or maintenance. Mechanistically, USP22 loss during reprogramming downregulates fibroblast-specific genes while activating pluripotency-associated genes, including DNMT3L, LIN28A, SOX2, and GDF3. Additionally, USP22 loss enhances reprogramming efficiency under naïve stem cell conditions. These findings reveal an unrecognized role for USP22 in maintaining somatic cell identity and repressing pluripotency genes, highlighting its potential as a target to improve reprogramming efficiency.
将体细胞重编程为诱导多能干细胞（iPSC）的细胞自主障碍仍知之甚少。通过聚焦的CRISPR-Cas9筛选，我们确定泛素特异性肽酶22（USP22）是人类iPSC衍生的关键染色质障碍。抑制USP22可显著提高重编程效率。令人惊讶的是，如通过模块特异性敲除和基因拯救实验所示，这种效应可能独立于USP22的去泛素酶活性或其与SAGA复合物的关联。iPSC的衍生或维持不需要USP22。从机制上讲，重编程过程中USP22的缺失下调成纤维细胞特异性基因，同时激活多能性相关基因，包括DNMT3L、LIN28A、SOX2和GDF3。此外，在原始干细胞条件下，USP22的缺失提高了重编程效率。这些发现揭示了USP22在维持体细胞身份和抑制多能性基因方面未被认识的作用，突出了其作为提高重编程效率靶点的潜力。
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