美国索尔克生物研究所的Joseph R. Ecker和Jesse R. Dixon等研究人员合作，对单个人类细胞中的三维基因组结构和DNA甲基化进行了同时描绘。这一研究成果2019年9月9日在线发表在《自然—方法学》上。

研究人员表示，动态三维染色质构象是发育和疾病过程中基因调控的关键机制。尽管如此，从具有细胞类型特异性分辨率的复杂组织中，分析三维基因组结构仍然具有挑战性。最近的努力已经证明，使用单细胞测定，可以在复杂组织中解析细胞类型特异性表观基因组特征。然而，尚不清楚单细胞染色质构象捕获（3C）或Hi-C谱是否能够有效地鉴定细胞类型，并重建细胞类型特异性染色质构象图。

为了应对这些挑战，研究人员开发了单核甲基-3C测序，以捕获染色质组织和DNA甲基化信息，并稳定地分离异质细胞类型。将该方法应用于4200多个人类脑前额叶皮质细胞，研究人员用14种皮质细胞类型重建出细胞类型特异性染色质构象图。这些数据揭示了细胞类型特异性染色质构象，与差异DNA甲基化之间的全基因组关联，表明调节基因表达的表观遗传过程之间的普遍相互作用。

附：英文原文

Title: Simultaneous profiling of 3D genome structure and DNA methylation in single human cells

Author: Dong-Sung Lee, Chongyuan Luo, Jingtian Zhou, Sahaana Chandran, Angeline Rivkin, Anna Bartlett, Joseph R. Nery, Conor Fitzpatrick, Carolyn OConnor, Jesse R. Dixon, Joseph R. Ecker

Issue&Volume: 2019-09-09

Abstract: Dynamic three-dimensional chromatin conformation is a critical mechanism for gene regulation during development and disease. Despite this, profiling of three-dimensional genome structure from complex tissues with cell-type specific resolution remains challenging. Recent efforts have demonstrated that cell-type specific epigenomic features can be resolved in complex tissues using single-cell assays. However, it remains unclear whether single-cell chromatin conformation capture (3C) or Hi-C profiles can effectively identify cell types and reconstruct cell-type specific chromatin conformation maps. To address these challenges, we have developed single-nucleus methyl-3C sequencing to capture chromatin organization and DNA methylation information and robustly separate heterogeneous cell types. Applying this method to >4,200 single human brain prefrontal cortex cells, we reconstruct cell-type specific chromatin conformation maps from 14 cortical cell types. These datasets reveal the genome-wide association between cell-type specific chromatin conformation and differential DNA methylation, suggesting pervasive interactions between epigenetic processes regulating gene expression. Single-nucleus methyl-3C sequencing jointly interrogates 3D chromatin organization and DNA methylation in human cells, and these joint measurements more accurately distinguish different cell types than either unimodal method.

DOI: 10.1038/s41592-019-0547-z

Source: https://www.nature.com/articles/s41592-019-0547-z