小柯机器人

美国纪念斯隆凯特林癌症研究所Samuel F. Bakhoum等研究人员合作发现微核中染色体运输带来的表观遗传失调。该研究于2023年6月7日在线发表于国际一流学术期刊《自然》。

研究人员表明，有丝分裂染色体的错位、它们在微核中的隔离以及随后微核膜的破裂都会严重破坏正常的组蛋白翻译后修饰（PTM），这种现象在人类和小鼠以及癌症和非转化细胞中都是保守的。有些组蛋白PTM的变化是由于微核膜的破裂而发生的，而有些则是在微核形成之前从有丝分裂的异常中继承下来的。

利用正交方法，研究人员证明微核在染色质可及性方面表现出广泛的差异，在启动子和远端或基因间区域之间有强烈的位置偏向，与观察到的组蛋白PTM的重新分布相一致。诱导CIN会导致广泛的表观遗传失调，在微核中运输的染色体在被重新纳入主核后很长一段时间内，其可及性会出现可遗传的异常。因此，除了改变基因组拷贝数外，染色体不稳定（CIN）还能促进表观遗传学的重新编程和癌症的异质性。

据了解，CIN和表观遗传学改变是晚期和转移性癌症的特征，但它们是否有机制上的联系尚不清楚。

附：英文原文

Title: Epigenetic dysregulation from chromosomal transit in micronuclei

Author: Agustinus, Albert S., Al-Rawi, Duaa, Dameracharla, Bhargavi, Raviram, Ramya, Jones, Bailey S. C. L., Stransky, Stephanie, Scipioni, Lorenzo, Luebeck, Jens, Di Bona, Melody, Norkunaite, Danguole, Myers, Robert M., Duran, Mercedes, Choi, Seongmin, Weigelt, Britta, Yomtoubian, Shira, McPherson, Andrew, Toufektchan, Elonore, Keuper, Kristina, Mischel, Paul S., Mittal, Vivek, Shah, Sohrab P., Maciejowski, John, Storchova, Zuzana, Gratton, Enrico, Ly, Peter, Landau, Dan, Bakhoum, Mathieu F., Koche, Richard P., Sidoli, Simone, Bafna, Vineet, David, Yael, Bakhoum, Samuel F.

Issue&Volume: 2023-06-07

Abstract: Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1,2,3,4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.

DOI: 10.1038/s41586-023-06084-7

Source: https://www.nature.com/articles/s41586-023-06084-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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