3D disorganization and rearrangement of genome provide insights into pathogenesis of NAFLD by integrated Hi-C,Nanopore,and RNA sequencing

• 作者: Lina Xu Lianhong Yin Yan Qi Xuemei Tan Meng Gao Jinyong Peng
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（10）
• 所属期刊栏目: Original articles
• 页码范围: 3150-3164
• 页数: 15页
• 语种: 英文

摘要

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 chro-matin interaction map was generated to examine different 3D genome hierarchies including A/B compart-ments,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 chro-matin 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 candi-date 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 frame-work for NAFLD therapy.