小柯机器人

美国纽约西奈山伊坎医学院Schahram Akbarian和Panos Roussos团队合作取得一项新成果。他们揭示在一大批精神分裂症 (SCZ)和双相情感障碍患者的大脑中，染色质域的改变与3D基因组组织有关。相关论文于2022年3月24日发表于国际顶尖学术期刊《自然—神经科学》杂志上。

他们利用从388 名对照和 351 名被诊断患有SCZ或双相情感障碍的个体中生成的 H3-27位赖氨酸乙酰化和 H3-4位赖氨酸三甲基化谱，为成人前额叶皮层构建了富含启动子和增强子的核小体组蛋白修饰图谱(BD) (n = 739)。他们绘制了数千个顺式调控域 (CRD)，揭示了细粒度的 104-106-碱基对 (bp)染色体组织，通过开放/抑制性染色体环境和核拓扑结构牢固地整合到 Hi-C 拓扑相关域分层中。大量的高乙酰化 CRD 富集了 SCZ 的遗传力，具有控制胎儿发育和谷氨酸能神经元信号传导的调节序列的显著表现。因此，SCZ 和 BD 大脑显示组装成千碱基到兆碱基尺度染色体结构域的风险相关调节序列的协调失调。

研究人员表示，染色体组织，从 147 个bp核小体扩展到包含多个转录单位的兆碱基范围的结构域，包括精神特征的遗传基因座，在人类大脑中很大程度上仍未探索。

附：英文原文

Title: Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains

Author: Girdhar, Kiran, Hoffman, Gabriel E., Bendl, Jaroslav, Rahman, Samir, Dong, Pengfei, Liao, Will, Hauberg, Mads E., Sloofman, Laura, Brown, Leanne, Devillers, Olivia, Kassim, Bibi S., Wiseman, Jennifer R., Park, Royce, Zharovsky, Elizabeth, Jacobov, Rivky, Flatow, Elie, Kozlenkov, Alexey, Gilgenast, Thomas, Johnson, Jessica S., Couto, Lizette, Peters, Mette A., Phillips-Cremins, Jennifer E., Hahn, Chang-Gyu, Gur, Raquel E., Tamminga, Carol A., Lewis, David A., Haroutunian, Vahram, Dracheva, Stella, Lipska, Barbara K., Marenco, Stefano, Kundakovic, Marija, Fullard, John F., Jiang, Yan, Roussos, Panos, Akbarian, Schahram

Issue&Volume: 2022-03-24

Abstract: Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n=739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 104–106-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.

DOI: 10.1038/s41593-022-01032-6

Source: https://www.nature.com/articles/s41593-022-01032-6

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex