Jing Xiong1,2, Tongyu Liu2, Lin Mi2, Henry Kuang2, Xuelian Xiong2, Zhimin Chen2, Siming Li2, Jiandie D Lin2. 1. Department of Pharmacology, School of Basic Medicine, Nanjing Medical University, Nanjing, Jiangsu, China. 2. Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI.
Abstract
BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is characterized by liver injury, inflammation, and fibrosis. NASH pathogenesis is linked to reprogramming of chromatin landscape in the liver that predisposes hepatocytes to stress-induced tissue injury. However, the molecular nature of the putative checkpoint that maintains chromatin architecture and preserves hepatocyte health remains elusive. APPROACH AND RESULTS: Here we show that heterogeneous nuclear ribonucleoprotein U (hnRNPU), a nuclear matrix protein that governs chromatin architecture and gene transcription, is a critical factor that couples chromatin disruption to NASH pathogenesis. RNA-seq and chromatin immunoprecipitation-seq studies revealed an extensive overlap between hnRNPU occupancy and altered gene expression during NASH. Hepatocyte-specific inactivation of hnRNPU disrupted liver chromatin accessibility, activated molecular signature of NASH, and sensitized mice to diet-induced NASH pathogenesis. Mechanistically, hnRNPU deficiency stimulated the expression of a truncated isoform of TrkB (TRKB-T1) that promotes inflammatory signaling in hepatocytes and stress-induced cell death. Brain-derived neurotrophic factor treatment reduced membrane TRKB-T1 protein and protected mice from diet-induced NASH. CONCLUSIONS: These findings illustrate a mechanism through which disruptions of chromatin architecture drive the emergence of disease-specific signaling patterns that promote liver injury and exacerbate NASH pathogenesis.
BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is characterized by liver injury, inflammation, and fibrosis. NASH pathogenesis is linked to reprogramming of chromatin landscape in the liver that predisposes hepatocytes to stress-induced tissue injury. However, the molecular nature of the putative checkpoint that maintains chromatin architecture and preserves hepatocyte health remains elusive. APPROACH AND RESULTS: Here we show that heterogeneous nuclear ribonucleoprotein U (hnRNPU), a nuclear matrix protein that governs chromatin architecture and gene transcription, is a critical factor that couples chromatin disruption to NASH pathogenesis. RNA-seq and chromatin immunoprecipitation-seq studies revealed an extensive overlap between hnRNPU occupancy and altered gene expression during NASH. Hepatocyte-specific inactivation of hnRNPU disrupted liver chromatin accessibility, activated molecular signature of NASH, and sensitized mice to diet-induced NASH pathogenesis. Mechanistically, hnRNPU deficiency stimulated the expression of a truncated isoform of TrkB (TRKB-T1) that promotes inflammatory signaling in hepatocytes and stress-induced cell death. Brain-derived neurotrophic factor treatment reduced membrane TRKB-T1 protein and protected mice from diet-induced NASH. CONCLUSIONS: These findings illustrate a mechanism through which disruptions of chromatin architecture drive the emergence of disease-specific signaling patterns that promote liver injury and exacerbate NASH pathogenesis.
Authors: Kunimasa Ohta; Giuseppe Lupo; Sei Kuriyama; Roger Keynes; Christine E Holt; William A Harris; Hideaki Tanaka; Shin-Ichi Ohnuma Journal: Dev Cell Date: 2004-09 Impact factor: 12.270
Authors: Philippe Lefebvre; Fanny Lalloyer; Eric Baugé; Michal Pawlak; Céline Gheeraert; Hélène Dehondt; Jonathan Vanhoutte; Eloise Woitrain; Nathalie Hennuyer; Claire Mazuy; Marie Bobowski-Gérard; Francesco Paolo Zummo; Bruno Derudas; Ann Driessen; Guy Hubens; Luisa Vonghia; Wilhelmus J Kwanten; Peter Michielsen; Thomas Vanwolleghem; Jérôme Eeckhoute; An Verrijken; Luc Van Gaal; Sven Francque; Bart Staels Journal: JCI Insight Date: 2017-07-06