Specificity in Circadian Clock Feedback from Targeted Reconstitution of the NuRD Corepressor
Specificity in Circadian Clock Feedback from Targeted Reconstitution of the NuRD Corepressor
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DOI：
10.1016/j.molcel.2014.10.017
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发表时间：
2014-12-18
期刊：
影响因子：
16
通讯作者：
Weitz, Charles J.
中科院分区：
文献类型：
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作者：
Kim, Jin Young;Kwak, Pieter Bas;Weitz, Charles J.
哺乳动物的昼夜节律是由负反馈环产生的，其中PERIOD（PER）蛋白积累，形成大的核复合物（PER复合物），并结合转录因子CLOCK-BMAL 1，抑制其自身的表达。我们发现，小鼠PER复合物包括Mi-2/核小体重塑和脱乙酰酶（NuRD）转录辅阻遏物。出乎意料的是，两个NuRD亚基CHD 4和MTA 2与CLOCK-BMAL 1组成型相关，其中CHD 4起促进CLOCK-BMAL 1转录活性的作用。在负反馈开始时，PER复合物将剩余的互补NuRD亚基递送至DNA结合的CLOCK-BMAL 1，从而重建对于昼夜节律转录反馈和时钟功能重要的NuRD辅阻遏物。PER复合物因此仅在成功靶向CLOCK-BMAL 1后获得完全阻遏物活性。我们的研究结果表明，尽管其依赖于通用转录调节因子，但时钟中是如何产生特异性的，并揭示了昼夜节律反馈回路的正负肢之间存在积极的沟通。
Mammalian circadian rhythms are generated by a negative feedback loop in which PERIOD (PER) proteins accumulate, form a large nuclear complex (PER complex), and bind the transcription factor CLOCK-BMAL1, repressing their own expression. We found that mouse PER complexes include the Mi-2/nucleosome remodelling and deacetylase (NuRD) transcriptional corepressor. Unexpectedly, two NuRD subunits, CHD4 and MTA2, constitutively associate with CLOCK-BMAL1, with CHD4 functioning to promote CLOCK-BMAL1 transcriptional activity. At the onset of negative feedback, the PER complex delivers the remaining complementary NuRD subunits to DNA-bound CLOCK-BMAL1, thereby reconstituting a NuRD corepressor that is important for circadian transcriptional feedback and clock function. The PER complex thus acquires full repressor activity only upon successful targeting of CLOCK-BMAL1. Our results show how specificity is generated in the clock despite its dependence on generic transcriptional regulators and reveal the existence of active communication between the positive and negative limbs of the circadian feedback loop.