染色质的三维(3D)构象是基因表达精确调节的组成部分。非酒精性脂肪性肝病(NAFLD)的3D基因组和基因组变异在很大程度上是未知的,尽管它们在细胞功能和生理过程中起着关键作用。高通量染色体构象捕获(Hi-C),纳米孔测序,在正常和NAFLD小鼠的肝脏上进行RNA测序(RNA-seq)测定。生成高分辨率3D染色质相互作用图,以检查包括A/B区室在内的不同3D基因组层次结构。拓扑关联域(TAD),和Hi-C的染色质循环,和全基因组测序通过纳米孔测序识别结构变异(SV)和拷贝数变异(CNV)。我们确定了基因组中数千个区域在3D染色质组织和基因组重排方面的变异,在正常和NAFLD小鼠之间,并揭示基因失调经常伴随着这些变异。在NAFLD中鉴定出候选靶基因,受基因重排和空间组织破坏的影响。我们的数据为NAFLD研究提供了高分辨率的3D基因组相互作用资源,揭示了基因重排之间的关系,空间组织破坏,和基因调控,并确定了与NAFLD发病机制相关的这些变异的候选基因。新发现为NAFLD发病机制提供了新的见解,并为NAFLD治疗提供了新的概念框架。
The three-dimensional (3D) conformation of chromatin is integral to the precise regulation of gene expression. The 3D genome and genomic variations in non-alcoholic fatty liver disease (NAFLD) are largely unknown, despite their key roles in cellular function and physiological processes. High-throughput chromosome conformation capture (Hi-C), Nanopore sequencing, and RNA-sequencing (RNA-seq) assays were performed on the liver of normal and NAFLD mice. A high-resolution 3D chromatin interaction map was generated to examine different 3D genome hierarchies including A/B compartments, topologically associated domains (TADs), and chromatin loops by Hi-C, and whole genome sequencing identifying structural variations (SVs) and copy number variations (CNVs) by Nanopore sequencing. We identified variations in thousands of regions across the genome with respect to 3D chromatin organization and genomic rearrangements, between normal and NAFLD mice, and revealed gene dysregulation frequently accompanied by these variations. Candidate target genes were identified in NAFLD, impacted by genetic rearrangements and spatial organization disruption. Our data provide a high-resolution 3D genome interaction resource for NAFLD investigations, revealed the relationship among genetic rearrangements, spatial organization disruption, and gene regulation, and identified candidate genes associated with these variations implicated in the pathogenesis of NAFLD. The newly findings offer insights into novel mechanisms of NAFLD pathogenesis and can provide a new conceptual framework for NAFLD therapy.