Peptidylarginine deiminase 1-catalyzed histone citrullination is essential for early embryo development.
Peptidylarginine deiminase 1-catalyzed histone citrullination is essential for early embryo development.
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肽基精氨酸脱亚胺酶 1 催化的组蛋白瓜氨酸化对于早期胚胎发育至关重要
DOI：
10.1038/srep38727
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发表时间：
2016-12-08
影响因子：
4.6
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Zhang X;Liu X;Zhang M;Li T;Muth A;Thompson PR;Coonrod SA;Zhang X
肽基精氨酸脱亚胺酶（PADI）越来越多地与通过组蛋白瓜氨酸调节染色质结构和基因活性相关。作为PADI家族成员之一，PADI 1主要在表皮和子宫中表达，其中角质形成细胞中的蛋白质被认为通过瓜氨酸化丝蛋白促进分化。然而，PADI 1在植入前发育中的作用尚未得到解决。使用Padi 1特异性抑制剂和Padi 1-morpholino敲低，我们发现在2-和4-细胞胚胎中，H4 R3和H3 R2/8/17处组蛋白尾部的瓜氨酸显著减少。与这一观察结果一致，在PADI 1耗尽或PADI 1酶活性抑制后，早期胚胎发育也在4细胞阶段停滞。此外，通过采用5-乙炔基尿苷（EU）掺入分析，消融PADI 1功能导致整体转录活性的急剧下降，与在Padi 1敲低或抑制PADI 1的2-或4-细胞期胚胎中观察到的Ser 2处RNA Pol II磷酸化水平降低密切相关。因此，我们的数据揭示了PADI 1在早期胚胎发育过渡期间通过催化组蛋白尾部瓜氨酸酶的新功能，这有助于早期胚胎基因组的反式激活。
Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos. Consistent with this observation, early embryo development was also arrested at the 4-cell stage upon depletion of PADI1 or inhibition of PADI1 enzyme activity. Additionally, by employing 5-ethynyl uridine (EU) incorporation analysis, ablation of PADI1 function led to a dramatic decrease in overall transcriptional activity, correlating well with the reduced levels of phosphorylation of RNA Pol II at Ser2 observed at 2- or 4-cell stage of embryos under Padi1 knockdown or inhibiting PADI1. Thus, our data reveal a novel function of PADI1 during early embryo development transitions by catalyzing histone tail citrullination, which facilitates early embryo genome transactivation.
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