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.

蛋白精氨酸脱亚胺酶 4 (PAD4) 促进核心组蛋白 H3 和 H4 的翻译后瓜氨酸化。虽然这种修饰的精确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有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，组蛋白的亲核侧链（特别是精氨酸）会发生甲基乙二醛（MGO）诱导的糖基化。这些非酶加合物通过与酶修饰竞争来改变染色质结构和表观遗传景观，并改变纤维的整体生物物理特性。在此，我们报道 PAD4 通过保护反应性精氨酸位点以及将已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，我们发现，与去糖酶 DJ-1 类似，PAD4 在乳腺癌肿瘤中过度表达，并且组蛋白瓜氨酸化上调，这表明与 PAD4 的致癌特性存在额外的机制联系。