Nipped-A regulates the Drosophila circadian clock via histone deubiquitination
Nipped-A regulates the Drosophila circadian clock via histone deubiquitination
复制标题
Nipped-A 通过组蛋白去泛素化调节果蝇生物钟
DOI：
10.15252/embj.2018101259
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发表时间：
2019-09-19
期刊：
影响因子：
11.4
通讯作者：
Zhang, Luoying
中科院分区：
文献类型：
--
作者：
Bu, Bei;Chen, Lixia;Zhang, Luoying
精神疾病通常伴有昼夜节律紊乱，但其分子基础在很大程度上仍不清楚。为了解决这个问题，我们筛选了先前报道的与精神疾病相关的基因，发现与精神分裂症相关的TRRAP基因参与昼夜节律调节。敲除人类TRRAP在果蝇中的同源基因Nipped-A，会导致果蝇运动节律周期延长。分子分析表明，NIPPED-A通过增加核心时钟基因timeless （tim）和Par结构域蛋白1 epsilon （Pdp1 epsilon）的mRNA和蛋白质水平来设定时钟的速度。此外，我们发现NIPPED-A可能通过转录共激活剂Spt-Ada-Gcn5乙酰转移酶复合物的去泛素化模块促进组蛋白H2B的去泛素化，从而促进了tim和Pdp1 epsilon的转录。综上所述，这些发现揭示了niped - a在生物钟表观遗传调控中的新作用。
Psychiatric diseases are often accompanied by circadian disruptions, but the molecular underpinnings remain largely unclear. To address this, we screened genes that have been previously reported to be associated with psychiatric diseases and found that TRRAP, a gene associated with schizophrenia, is involved in circadian rhythm regulation. Knocking down Nipped-A, the Drosophila homolog of human TRRAP, leads to lengthened period of locomotor rhythms in flies. Molecular analysis demonstrates that NIPPED-A sets the pace of the clock by increasing the mRNA and protein levels of core clock genes timeless (tim) and Par domain protein 1 epsilon (Pdp1 epsilon). Furthermore, we found that NIPPED-A promotes the transcription of tim and Pdp1 epsilon possibly by facilitating deubiquitination of histone H2B via the deubiquitination module of the transcription co-activator Spt-Ada-Gcn5 acetyltransferase complex. Taken together, these findings reveal a novel role for NIPPED-A in epigenetic regulation of the clock.