脂肪肝
表观遗传学
脂肪性肝炎
组蛋白
增强子
染色质免疫沉淀
生物
乙酰化
转录组
癌症研究
细胞生物学
基因
内科学
遗传学
转录因子
基因表达
医学
发起人
疾病
作者
Yaling Zhu,Leilei Meng,Jinhu Ma,Xianjun Yuan,Shuwen Chen,Xinrui Yi,Xinyu Li,Yi Wang,Yunshu Tang,Min Xue,Meizi Zhu,Peng Jin,Xuejin Lu,Jingjing Huang,Chong Wang,Zichen Song,Kang Zheng,Qingqing Dai,Fan Huang,Haoshu Fang
标识
DOI:10.24272/j.issn.2095-8137.2023.022
摘要
Non-alcoholic fatty liver disease (NAFLD) has been widely reported to have a potential association with LBP (Lipopolysaccharide-binding protein) mutation. However, the mechanisms, especially epigenetic mechanisms underpinning the association remain elusive. Herein, we constructed LBP-/- rats with NAFLD and performed integrative analysis of targeting-active enhancer H3K27ac chromatin immunoprecipitation coupled with high-throughput sequencing and transcriptomic sequencing to explore the potential epigenetic pathomechanisms of active enhancer in the exacerbation of NAFLD upon LBP deficiency. Intriguingly, we found that LBP-/- could reduce inflammatory response but markedly deteriorate HFD-induced NAFLD in rats, with abundant alterations of histone acetylome and regulatory transcriptome. In total, 1,128 differential enhancer-target genes significantly enriched in cholesterol metabolic process and fatty acid metabolic process were identified with | Cor (peak-gene correlation) | > 0.5 and a | log2 (fold change) | > 1.5 between WT and LBP-/- NAFLD rats. Notably, based on our integrative analysis method, we screened out TF C/EBPβ (CCAAT/enhancer-binding protein β) as a pivotal contributor to dysregulated histone acetylome H3K27ac and lipid metabolism gene SCD as a downstream effector to exacerbate NAFLD. Thus, this study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from the perspective of epigenetics, but identifies key TF C/EBPβ and hub functional gene SCD as potential regulators that may serve as possible therapeutic targets.
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