The transcription factor ZNF469 regulates collagen production in liver fibrosis [Cohort_CUTRUN_H3K27ac]. The transcription factor ZNF469 regulates collagen production in liver fibrosis [Cohort_CUTRUN_H3K27ac]

Non-alcoholic fatty liver disease (NAFLD)—characterized by excess accumulation of fat in the liver—now affects one third of the world’s population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis. Overall design: Human Liver biopsies from patients referred for bariatric surgery. Both males and females are included.

非酒精性脂肪肝病（Non-alcoholic fatty liver disease, NAFLD）以肝脏内脂肪过度蓄积为核心特征，目前已影响全球三分之一的人口。随着NAFLD病情进展，包括胶原蛋白在内的细胞外基质成分会在肝脏内蓄积，引发组织纤维化——这是决定疾病严重程度与患者死亡率的关键危险因素。为鉴定纤维化的转录调控因子，研究团队对涵盖NAFLD全组织病理谱的深度表型队列中的108例人类肝活检样本的匹配转录组与表观基因组进行分析，通过计算推断了与纤维化相关的转录因子（Transcription factors, TFs）的活性。对筛选出的前100个TF开展基于CRISPR的基因敲除实验后，研究人员证实ZNF469是原代人肝星状细胞（primary human hepatic stellate cells, HSCs）中胶原蛋白表达的调控因子。功能获得与功能丧失实验表明，ZNF469可通过直接结合基因本体及调控元件，调控胶原蛋白基因与基质稳态相关基因的表达。通过将人类肝活检样本的多组学大规模谱分析与多轮实验验证相结合，研究团队证明ZNF469是肝星状细胞中胶原蛋白的转录调控因子。综上，本研究数据将ZNF469定为此前未被发现的NAFLD相关肝纤维化调控因子。整体实验设计：招募因减重手术就诊的患者的人类肝活检样本，研究纳入男性与女性受试者。