Citrullination regulates pluripotency and histone H1 binding to chromatin.
Citrullination regulates pluripotency and histone H1 binding to chromatin.
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DOI：
10.1038/nature12942
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发表时间：
2014-03-06
期刊：
影响因子：
64.8
通讯作者：
Kouzarides T
中科院分区：
文献类型：
--
作者：
Christophorou MA;Castelo-Branco G;Halley-Stott RP;Oliveira CS;Loos R;Radzisheuskaya A;Mowen KA;Bertone P;Silva JC;Zernicka-Goetz M;Nielsen ML;Gurdon JB;Kouzarides T
瓜氨酸是蛋白质中精氨酸残基翻译后转化为非编码氨基酸瓜氨酸。这种改性导致正电荷的损失和氢键结合能力的降低。它是由一个小家族的组织特异性脊椎动物酶称为肽基精氨酸脱亚胺酶（PADI）2，并与发展的各种病理状态，如自身免疫，癌症，神经退行性疾病，朊病毒疾病和血栓形成。尽管如此，瓜氨酸的生理功能仍然不明确，尽管核心组蛋白的瓜氨酸与转录调控和DNA损伤反应有关。PADI 4（或PAD 4/PADV）是唯一具有核定位信号的PADI，先前显示其在骨髓细胞中起作用，其中其在对感染的先天免疫应答期间介导深度染色质解浓缩。在这里，我们表明，PADI 4的表达和酶活性也诱导条件下的基态多能性和重编程过程中。PADI 4是多能性转录网络的一部分，与关键干细胞基因的调控元件结合并激活其表达。它的抑制降低了早期小鼠胚胎中多能细胞的百分比，并显着降低了重编程效率。使用公正的蛋白质组学方法，我们确定接头组蛋白H1的变体，这是参与生成紧凑的染色质，作为新的PADI 4基板。瓜氨酸在H1的DNA结合位点内的单个精氨酸残基导致其从染色质和整体染色质解凝聚的置换。总之，这些结果揭示了瓜氨酸在调节多能性中的作用，并为瓜氨酸如何调节染色质致密化提供了新的机制见解。
Citrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline. This modification leads to the loss of a positive charge and reduction in hydrogen bonding ability. It is carried out by a small family of tissue-specific vertebrate enzymes called peptidylarginine deiminases (PADIs)2 and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis. Nonetheless, the physiological functions of citrullination remain ill-defined, though citrullination of core histones has been linked to transcriptional regulation and the DNA damage response. PADI4 (or PAD4/PADV), the only PADI with a nuclear localization signal, was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection. Here we show that the expression and enzymatic activity of PADI4 are also induced under conditions of ground state pluripotency and during reprogramming. PADI4 is part of the pluripotency transcriptional network, binding to regulatory elements of key stem cell genes and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin, as novel PADI4 substrates. Citrullination of a single arginine residue within the DNA binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic insights into how citrullination regulates chromatin compaction.