Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in HSCs.

Autor:	Sun C; Department of Medicine, Division of Gastroenterology, Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA., Zhou C; Department of Population and Quantitative Health Sciences, Chan Medical School, University of Massachusetts, Worcester, Massachusetts USA., Daneshvar K; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Ben Saad A; Department of Medicine, Division of Gastroenterology, Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA., Kratkiewicz AJ; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Toles BJ; Department of Medicine, Division of Gastroenterology, Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA., Arghiani N; Department of Medicine, Division of Gastroenterology, Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA., Hess A; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Chen JY; Department of Medicine, Liver Center, University of California, San Francisco, California, USA., Pondick JV; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., York SR; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Li W; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Moran SP; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Gentile SD; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute, Cambridge, Massachusetts, USA., Rahman RU; Department of Medicine, Division of Gastroenterology, Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA.; Broad Institute, Cambridge, Massachusetts, USA., Li Z; Department of Population and Quantitative Health Sciences, Chan Medical School, University of Massachusetts, Worcester, Massachusetts USA., Zhou P; Department of Population and Quantitative Health Sciences, Chan Medical School, University of Massachusetts, Worcester, Massachusetts USA., Sparks RP; Department of Medicine, Division of Gastroenterology, Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA., Habboub T; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Kim BM; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Choi MY; Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Affo S; Department of Liver, Digestive System, and Metabolism, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain., Schwabe RF; Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA., Popov YV; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Mullen AC; Department of Medicine, Division of Gastroenterology, Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA.; Broad Institute, Cambridge, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Hepatology (Baltimore, Md.) [Hepatology] 2024 Apr 02. Date of Electronic Publication: 2024 Apr 02.
DOI:	10.1097/HEP.0000000000000822
Abstrakt:	Background and Aims: Fibrosis is the common end point for all forms of chronic liver injury, and the progression of fibrosis leads to the development of end-stage liver disease. Activation of HSCs and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix proteins that form the fibrotic scar. Long noncoding RNAs regulate the activity of HSCs and provide targets for fibrotic therapies. Approach and Results: We identified long noncoding RNA TILAM located near COL1A1 , expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates the expression of COL1A1 and other extracellular matrix genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog ( Tilam ), generated Tilam- deficient green fluorescent protein-reporter mice, and challenged these mice in 2 different models of liver fibrosis. Single-cell data and analysis of single-data and analysis of Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Tilam -deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated the development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with promyelocytic leukemia nuclear body scaffold protein to regulate a feedback loop by which TGF-β2 reinforces TILAM expression and nuclear localization of promyelocytic leukemia nuclear body scaffold protein to promote the fibrotic activity of HSCs. Conclusions: TILAM is activated in HSCs with liver injury and interacts with promyelocytic leukemia nuclear body scaffold protein to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end-stage liver disease. (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
Databáze:	MEDLINE
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