Defective transcription initiation causes postnatal growth failure in a mouse model of nucleotide excision repair (NER) progeria
Defective transcription initiation causes postnatal growth failure in a mouse model of nucleotide excision repair (NER) progeria
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DOI：
10.1073/pnas.1114941109
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发表时间：
2012-02-21
影响因子：
11.1
通讯作者：
Garinis, George A.
中科院分区：
文献类型：
--
作者：
Kamileri, Irene;Karakasilioti, Ismene;Garinis, George A.
核苷酸切除修复（NER）缺陷与癌症、发育障碍和神经退行性疾病有关。然而，除癌症外，NER 缺陷与发育异常之间的联系尚不清楚。在这里，我们证明 ERCC1-XPF NER 核酸内切酶在体内组装在活性启动子上，并促进哺乳动物发育过程中转录的染色质修饰。我们发现Ercc1(-/-)小鼠表现出与在转录起始中携带肝脏特异性转录因子II D (TFIID)缺陷的Taf10(-/-)动物惊人的生理、代谢和基因表达相似。启动子占据研究结合肝脏表达谱和体外分化细胞测定表明，ERCC1-XPF 与 TFIID 相互作用，并在体内与 POL II 和启动子上的基础转录机制组装。虽然 ERCC1-XPF 是与生长相关的基因的初始激活所必需的，但它对于持续转录来说是可有可无的。 ERCC1-XPF 在启动子上的募集伴随着启动子近端 DNA 去甲基化和与活跃肝转录相关的组蛋白标记。总的来说，这些数据揭示了 ERCC1/XPF 核酸内切酶在转录起始中的作用，确定了其对 NER 发育障碍的因果作用。
Nucleotide excision repair (NER) defects are associated with cancer, developmental disorders and neurodegeneration. However, with the exception of cancer, the links between defects in NER and developmental abnormalities are not well understood. Here, we show that the ERCC1-XPF NER endonuclease assembles on active promoters in vivo and facilitates chromatin modifications for transcription during mammalian development. We find that Ercc1(-/-) mice demonstrate striking physiological, metabolic and gene expression parallels with Taf10(-/-) animals carrying a liver-specific transcription factor II D (TFIID) defect in transcription initiation. Promoter occupancy studies combined with expression profiling in the liver and in vitro differentiation cell assays reveal that ERCC1-XPF interacts with TFIID and assembles with POL II and the basal transcription machinery on promoters in vivo. Whereas ERCC1-XPF is required for the initial activation of genes associated with growth, it is dispensable for ongoing transcription. Recruitment of ERCC1-XPF on promoters is accompanied by promoter-proximal DNA demethylation and histone marks associated with active hepatic transcription. Collectively, the data unveil a role of ERCC1/XPF endonuclease in transcription initiation establishing its causal contribution to NER developmental disorders.