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。虽然此修饰的精确表观遗传功能尚未解决，但已证明它与一般的染色质分解反应相关，并与精氨酸甲基化竞争。最近，我们发现在代谢应激条件下，组蛋白在亲核侧链（尤其是精氨酸）上受到甲基乙二醛（MGO）诱导的糖基化作用。这些非酶加合物通过与酶修饰竞争以及改变纤维的整体生物物理特性，改变了染色质结构和表观遗传景观。在这里，我们报道PAD4通过保护反应性精氨酸位点，以及通过将已经糖化的精氨酸残基转化为瓜氨酸来拮抗组蛋白MGO糖基化。