美国西奈山伊坎医学院Panos Roussos团队近期取得重要工作进展，他们研究绘制了阿尔茨海默病中皮层染色质可及性的三维图谱。相关论文2022年9月28日在线发表于《自然—神经科学》杂志上。

为了描述阿尔茨海默病（AD）中染色质可及性失调的特征，该团队从153例AD患者和56例对照组的颞上回和内嗅皮层分离的神经元和非神经元核中，生成了636个ATAC-seq文库。通过分析总计约200亿的阅读对，课题组扩展了人类大脑中已知的开放染色质区域（OCRs）的知识库，并确定了细胞类型特定的增强子-启动子相互作用。研究人员发现，可以利用OCR的个体间差异来识别顺式调控域（CRDs），这些调控域捕捉了基因组的三维结构（3D基因组）。他们确定了与AD相关的对染色质可及性、三维基因组和转录因子（TF）调节网络的影响。对于最受AD干扰的TFs之一，USF2，研究人员验证了它对溶酶体基因的调节作用。

总的来说，研究人员应用了一种系统的方法来理解三维基因组在AD中的作用。他们将所有数据作为在线资源提供，以进行广泛的基于社区的分析。

附：英文原文

Title: The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease

Author: Bendl, Jaroslav, Hauberg, Mads E., Girdhar, Kiran, Im, Eunju, Vicari, James M., Rahman, Samir, Fernando, Michael B., Townsley, Kayla G., Dong, Pengfei, Misir, Ruth, Kleopoulos, Steven P., Reach, Sarah M., Apontes, Pasha, Zeng, Biao, Zhang, Wen, Voloudakis, Georgios, Brennand, Kristen J., Nixon, Ralph A., Haroutunian, Vahram, Hoffman, Gabriel E., Fullard, John F., Roussos, Panos

Issue&Volume: 2022-09-28

Abstract: To characterize the dysregulation of chromatin accessibility in Alzheimer’s disease (AD), we generated 636 ATAC-seq libraries from neuronal and nonneuronal nuclei isolated from the superior temporal gyrus and entorhinal cortex of 153 AD cases and 56 controls. By analyzing a total of ~20 billion read pairs, we expanded the repertoire of known open chromatin regions (OCRs) in the human brain and identified cell-type-specific enhancer–promoter interactions. We show that interindividual variability in OCRs can be leveraged to identify cis-regulatory domains (CRDs) that capture the three-dimensional structure of the genome (3D genome). We identified AD-associated effects on chromatin accessibility, the 3D genome and transcription factor (TF) regulatory networks. For one of the most AD-perturbed TFs, USF2, we validated its regulatory effect on lysosomal genes. Overall, we applied a systematic approach to understanding the role of the 3D genome in AD. We provide all data as an online resource for widespread community-based analysis.

DOI: 10.1038/s41593-022-01166-7

Source: https://www.nature.com/articles/s41593-022-01166-7