Ho Jaclyn J, Cattoglio Claudia, McSwiggen David T, Tjian Robert, Fong Yick W
Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, California Institute for Regenerative Medicine Center of Excellence, University of California at Berkeley, Berkeley, California 94720, USA.
Howard Hughes Medical Institute, Berkeley, California 94720, USA.
Genes Dev. 2017 Apr 15;31(8):830-844. doi: 10.1101/gad.295741.116.
Faithful resetting of the epigenetic memory of a somatic cell to a pluripotent state during cellular reprogramming requires DNA methylation to silence somatic gene expression and dynamic DNA demethylation to activate pluripotency gene transcription. The removal of methylated cytosines requires the base excision repair enzyme TDG, but the mechanism by which TDG-dependent DNA demethylation occurs in a rapid and site-specific manner remains unclear. Here we show that the XPC DNA repair complex is a potent accelerator of global and locus-specific DNA demethylation in somatic and pluripotent stem cells. XPC cooperates with TDG genome-wide to stimulate the turnover of essential intermediates by overcoming slow TDG-abasic product dissociation during active DNA demethylation. We further establish that DNA demethylation induced by XPC expression in somatic cells overcomes an early epigenetic barrier in cellular reprogramming and facilitates the generation of more robust induced pluripotent stem cells, characterized by enhanced pluripotency-associated gene expression and self-renewal capacity. Taken together with our previous studies establishing the XPC complex as a transcriptional coactivator, our findings underscore two distinct but complementary mechanisms by which XPC influences gene regulation by coordinating efficient TDG-mediated DNA demethylation along with active transcription during somatic cell reprogramming.
在细胞重编程过程中，将体细胞的表观遗传记忆忠实地重置为多能状态需要DNA甲基化来沉默体细胞基因表达，以及动态DNA去甲基化来激活多能性基因转录。去除甲基化的胞嘧啶需要碱基切除修复酶TDG，但TDG依赖的DNA去甲基化以快速且位点特异性的方式发生的机制仍不清楚。在这里，我们表明XPC DNA修复复合物是体细胞和多能干细胞中全局和位点特异性DNA去甲基化的有力促进剂。XPC在全基因组范围内与TDG合作，通过克服活性DNA去甲基化过程中TDG-无碱基产物解离缓慢的问题，刺激必需中间体的周转。我们进一步证实，体细胞中XPC表达诱导的DNA去甲基化克服了细胞重编程中的早期表观遗传障碍，并促进了更强大的诱导多能干细胞的产生，其特征是多能性相关基因表达增强和自我更新能力提高。结合我们之前将XPC复合物确立为转录共激活因子的研究，我们的发现强调了XPC通过在体细胞重编程过程中协调有效的TDG介导的DNA去甲基化与活性转录来影响基因调控的两种不同但互补的机制。
