Chromatin Hyperacetylation Impacts Chromosome Folding by Forming a Nuclear Subcompartment.
Chromatin Hyperacetylation Impacts Chromosome Folding by Forming a Nuclear Subcompartment.
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染色质超乙酰化通过形成核亚区室影响染色体折叠。
DOI：
10.1016/j.molcel.2020.03.018
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发表时间：
2020
期刊：
影响因子：
16
通讯作者：
Eagen,KyleP
中科院分区：
文献类型：
--
作者：
Rosencrance,CelesteD;Ammouri,HaneenN;Yu,Qi;Ge,Tiffany;Rendleman,EmilyJ;Marshall,StacyA;Eagen,KyleP
描述染色体在超过一百万倍的长度尺度上如何折叠仍然是模糊的，相对于较小尺度的折叠成TADs，环和核小体。我们发现，而不是简单地展开染色质，组蛋白超乙酰化的结果，在遥远的基因组位点之间的相互作用，分开几十到几百兆碱基，即使在没有转录。这些超乙酰化的“巨核蛋白”由BRD 4-NUT融合癌蛋白形成，在染色体内和染色体之间相互作用，并形成相对于其他亚区室具有升高的基因活性的特定核亚区室。BRD 4-NUT的药理学降解导致巨蛋白的崩溃和它们之间的相互作用的减弱。相反，这些相互作用持续存在，并且在抑制RNA聚合酶II起始后形成新乙酰化区域之间的接触。因此，我们的结构-功能方法揭示了相同的生化组成的广泛的染色质结构域，独立于转录，形成核亚室，也表明改变染色体结构用于治疗人类疾病的潜力。
Delineating how chromosomes fold at length scales beyond one megabase remains obscure relative to smaller-scale folding into TADs, loops, and nucleosomes. We find that rather than simply unfolding chromatin, histone hyperacetylation results in interactions between distant genomic loci separated by tens to hundreds of megabases, even in the absence of transcription. These hyperacetylated "megadomains" are formed by the BRD4-NUT fusion oncoprotein, interact both within and between chromosomes, and form a specific nuclear subcompartment that has elevated gene activity with respect to other subcompartments. Pharmacological degradation of BRD4-NUT results in collapse of megadomains and attenuation of the interactions between them. In contrast, these interactions persist and contacts between newly acetylated regions are formed after inhibiting RNA polymerase II initiation. Our structure-function approach thus reveals that broad chromatin domains of identical biochemical composition, independent of transcription, form nuclear subcompartments, and also indicates the potential of altering chromosome structure for treating human disease.