Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Tri-Institutional PhD Program in Chemical Biology, New York, NY, 10065, USA.
Nat Commun. 2020 Jun 26;11(1):3241. doi: 10.1038/s41467-020-17066-y.
Protein arginine deiminase 4 (PAD4) facilitates the post-translational citrullination of the core histones H3 and H4. While the precise epigenetic function of this modification has not been resolved, it has been shown to associate with general chromatin decompaction and compete with arginine methylation. Recently, we found that histones are subjected to methylglyoxal (MGO)-induced glycation on nucleophilic side chains, particularly arginines, under metabolic stress conditions. These non-enzymatic adducts change chromatin architecture and the epigenetic landscape by competing with enzymatic modifications, as well as changing the overall biophysical properties of the fiber. Here, we report that PAD4 antagonizes histone MGO-glycation by protecting the reactive arginine sites, as well as by converting already-glycated arginine residues into citrulline. Moreover, we show that similar to the deglycase DJ-1, PAD4 is overexpressed and histone citrullination is upregulated in breast cancer tumors, suggesting an additional mechanistic link to PAD4's oncogenic properties.
蛋白质精氨酸脱亚氨酶 4（PAD4）促进核心组蛋白 H3 和 H4 的翻译后瓜氨酸化。虽然这种修饰的确切表观遗传功能尚未解决，但它已被证明与一般染色质解压缩和与精氨酸甲基化竞争有关。最近，我们发现组蛋白在代谢应激条件下，亲核侧链，特别是精氨酸，易受甲基乙二醛（MGO）诱导的糖化作用的影响。这些非酶加合物通过与酶修饰竞争以及改变纤维的整体物理特性来改变染色质结构和表观遗传景观。在这里，我们报告 PAD4 通过保护反应性精氨酸位点以及将已经糖化的精氨酸残基转化为瓜氨酸来拮抗组蛋白 MGO-糖化。此外，我们表明，类似于去糖基化酶 DJ-1，PAD4 在乳腺癌肿瘤中过度表达并且组蛋白瓜氨酸化上调，这表明 PAD4 的致癌特性存在另一种机制联系。
