Functional Connection between Deimination and Deacetylation of Histones
Functional Connection between Deimination and Deacetylation of Histones
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DOI：
10.1128/mcb.00285-09
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发表时间：
2009-09-15
影响因子：
5.3
通讯作者：
Fuks, Francois
中科院分区：
文献类型：
--
作者：
Denis, Helene;Deplus, Rachel;Fuks, Francois
组蛋白甲基化在调节染色质结构和功能中起着关键作用。最近鉴定的酶，拮抗或消除组蛋白甲基化提供了新的机会，欣赏组蛋白甲基化可塑性的调节表观遗传途径。肽基精氨酸脱亚胺酶4（PADI 4;也称为PAD 4）是第一个显示出拮抗组蛋白甲基化的酶。PADI 4作为组蛋白脱亚胺酶发挥作用，在组蛋白H3和H4尾部的特定位点将甲基精氨酸残基转化为瓜氨酸。这种活性与雌激素调节的pS2启动子的抑制有关。关于PADI 4如何沉默基因表达知之甚少。我们发现PADI 4与组蛋白去乙酰化酶1（HDAC 1）相关。动态染色质免疫沉淀分析表明，PADI 4和HDAC 1，以及相应的活动，协会周期和协调与pS2启动子在镇压阶段。HDAC 1的敲低导致H3瓜氨酸减少，同时组蛋白精氨酸甲基化增加。在HDAC 1水平降低和PADI 4水平略微降低的细胞中，这些作用更加明显。因此，我们的数据表明，PADI 4和HDAC 1合作，以产生一个抑制染色质环境的pS2启动子。这些发现进一步证实了“转录时钟”的概念，突出了组蛋白脱亚胺化和脱乙酰化之间的动态联系。
Histone methylation plays key roles in regulating chromatin structure and function. The recent identification of enzymes that antagonize or remove histone methylation offers new opportunities to appreciate histone methylation plasticity in the regulation of epigenetic pathways. Peptidylarginine deiminase 4 (PADI4; also known as PAD4) was the first enzyme shown to antagonize histone methylation. PADI4 functions as a histone deiminase converting a methylarginine residue to citrulline at specific sites on the tails of histones H3 and H4. This activity is linked to repression of the estrogen-regulated pS2 promoter. Very little is known as to how PADI4 silences gene expression. We show here that PADI4 associates with the histone deacetylase 1 (HDAC1). Kinetic chromatin immunoprecipitation assays revealed that PADI4 and HDAC1, and the corresponding activities, associate cyclically and coordinately with the pS2 promoter during repression phases. Knockdown of HDAC1 led to decreased H3 citrullination, concomitantly with increased histone arginine methylation. In cells with a reduced HDAC1 and a slightly decreased PADI4 level, these effects were more pronounced. Our data thus suggest that PADI4 and HDAC1 collaborate to generate a repressive chromatin environment on the pS2 promoter. These findings further substantiate the "transcriptional clock" concept, highlighting the dynamic connection between deimination and deacetylation of histones.