Abstract：
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Little is known about how gene expression and chromatin structure are regulated in NAFLD due to lack of suitable model. Ducks naturally develop fatty liver similar to serious human non-alcoholic fatty liver (NAFL) without adipose inflammation and liver fibrosis, thus serves as a good model for investigating molecular mechanisms of adipose metabolism and anti-inflammation. Here, we constructed a NAFLD model without adipose inflammation and liver fibrosis in ducks. By performing dynamic pathological and transcriptomic analyses, we identified critical genes involving in regulation of the NF-κB and MHCII signaling, which usually lead to adipose inflammation and liver fibrosis. We further generated dynamic three-dimensional chromatin maps during liver fatty formation and recovery. This showed that ducks enlarged hepatocyte cell nuclei to reduce inter-chromosomal interaction, decompress chromatin structure, and alter strength of intra-TAD and loop interactions during fatty liver formation. These changes partially contributed to the tight control the NF-κB and the MHCII signaling. Our analysis uncovers duck chromatin reorganization might be advantageous to maintain liver regenerative capacity and reduce adipose inflammation. These findings shed light on new strategies for NAFLD control.
摘要：
非酒精性脂肪性肝病（NAFLD）是慢性肝病的最常见形式。由于缺乏合适的模型，对NAFLD中基因表达和染色质结构的调控知之甚少。鸭子自然发展脂肪肝类似于严重的人类非酒精性脂肪肝（NAFL）无脂肪炎症和肝纤维化，因此可以作为研究脂肪代谢和抗炎分子机制的良好模型。这里,我们构建了鸭无脂肪炎症和肝纤维化的NAFLD模型。通过进行动态病理和转录组学分析，我们确定了涉及NF-κB和MHCII信号调节的关键基因，这通常会导致脂肪炎症和肝纤维化。我们进一步生成了肝脏脂肪形成和恢复过程中的动态三维染色质图。这表明鸭子增大肝细胞核以减少染色体间的相互作用，解压缩染色质结构，并改变脂肪肝形成过程中TAD内和环路相互作用的强度。这些变化部分有助于严格控制NF-κB和MHCII信号传导。我们的分析揭示了鸭染色质重组可能有利于维持肝脏再生能力和减少脂肪炎症。这些发现揭示了控制NAFLD的新策略。
