The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.
The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.
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DOI：
10.1016/j.cell.2015.06.060
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发表时间：
2015-07-30
期刊：
影响因子：
64.5
通讯作者：
Nolan PM
中科院分区：
文献类型：
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作者：
Parsons MJ;Brancaccio M;Sethi S;Maywood ES;Satija R;Edwards JK;Jagannath A;Couch Y;Finelli MJ;Smyllie NJ;Esapa C;Butler R;Barnard AR;Chesham JE;Saito S;Joynson G;Wells S;Foster RG;Oliver PL;Simon MM;Mallon AM;Hastings MH;Nolan PM
我们在SCN转录因子Zfhx3中发现了一个显性错义突变，称为短路（Zfhx3Sci），它加速了小鼠的昼夜运动节律。ZFHX3通过与靶基因中预测的AT基序的直接相互作用调节转录。突变蛋白在体外激活一致AT基序的能力下降。通过RNA测序，我们发现Zfhx3Sci/+ SCN对核心时钟基因的影响很小，而对SCN细胞间信号传导至关重要的神经肽的表达明显受到干扰。此外，突变体ZFHX3在这些神经肽基因的启动子中激活AT基序的能力下降。SCN切片的慢病毒转导表明，zfhx3介导的AT基序激活是昼夜节律的，在Zfhx3Sci/+ SCN切片中，这些振荡的幅度和稳健性降低。总之，通过克隆Zfhx3Sci，我们发现了一个决定行为和SCN分子节律周期和稳健性的昼夜转录轴。Zfhx3错义突变是短路（Zfhx3Sci）昼夜节律表型的基础Zfhx3Sci降低了Zfhx3通过AT基序激活转录的能力Zfhx3Sci表型与神经肽启动子中AT基序激活降低有关SCN的昼夜节律激活揭示了AT基序作为一种新的时钟调节的转录轴a转录因子在离散的成人下丘脑核中表达，包括视交叉上核。通过表达不同的神经肽能基因来调节体内的昼夜运动节律，以确保强劲的同步振荡和昼夜节律。
We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3Sci), which accelerates circadian locomotor rhythms in mice. ZFHX3 regulates transcription via direct interaction with predicted AT motifs in target genes. The mutant protein has a decreased ability to activate consensus AT motifs in vitro. Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3Sci/+ SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed. Moreover, mutant ZFHX3 had a decreased ability to activate AT motifs in the promoters of these neuropeptide genes. Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3Sci/+ SCN slices. In conclusion, by cloning Zfhx3Sci, we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms. Zfhx3 missense mutation underlies the short circuit (Zfhx3Sci) circadian phenotype Zfhx3Sci reduces the ability of ZFHX3 to activate transcription via AT motifs Zfhx3Sci phenotype is associated with decreased activation of AT motif in neuropeptide promoters Circadian activation in SCN reveals AT motif as a new clock-regulated transcriptional axis A transcription factor expressed in discrete adult hypothalamic nuclei, including the suprachiasmatic nucleus, regulates circadian locomotor rhythms in vivo through the expression of distinct neuropeptidergic genes to ensure robust synchronous oscillations and circadian rhythms.