Journal Article

The transcription factor ZNF469 regulates collagen production in liver fibrosis

Farber-Eger, Eric, Vissieres, Alexandra, Moulin, Pierre, Hoepfner, Dominic, Reyes, Alejandro, Knehr, Judith, Flynn, Charles R., Steinhauser, Sebastian, Liang, Jiancong, Buehler, Dennis P., Williams, Brandon, Altorfer, Marc, Rietsch, Amandine, Tropberger, Philipp, Bergling, Sebastian, Xiong, Yanhua, Wells, Quinn S., Voshol, Johannes, Mickanin, Craig, Nigsch, Florian, Wunderlin, Tiffany, Brown, Jonathan D., Estoppey, David, Pizzato, Nicolas, Müller, Miriam, Frederiksen, Mathias, Leroy, Nelly, Fodor, Barna D., English, Wayne J., Wu, Fabian, Sheng, Quanhu, Kolter, Christian, Davison, Lindsay M., Claerr, Isabelle, Wild, Sophia

2025

Overview

Metabolic dysfunction–associated steatotic liver disease (MASLD) — characterized by excess accumulation of fat in the liver — now affects one-third of the world’s population. As MASLD 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 MASLD. CRISPR-based genetic KO 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 MASLD-associated liver fibrosis.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Biopsy / Collagen / Collagen - biosynthesis / Collagen - genetics / Collagen - metabolism / CRISPR / Extracellular matrix / Fatty Liver - complications / Fatty Liver - genetics / Fatty Liver - metabolism / Fatty Liver - pathology / Fibrosis / Gastrointestinal surgery / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Genomes / Hepatic Stellate Cells - metabolism / Hepatology / Homeostasis / Hormone replacement therapy / Humans / Inflammation / Liver - metabolism / Liver - pathology / Liver cirrhosis / Liver Cirrhosis - genetics / Liver Cirrhosis - metabolism / Liver Cirrhosis - pathology / Liver diseases / Male / Metabolism / Mortality / Nonsteroidal anti-inflammatory drugs / Regulatory sequences / Stellate cells / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptome / Transcriptomes