Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease

Min Zhu; Tianshi Lu; Yuemeng Jia; Xin Luo; Purva Gopal; Lin Li; Mobolaji Odewole; Veronica Renteria; Amit G Singal; Younghoon Jang; Kai Ge; Sam C Wang; Mahsa Sorouri; Justin R Parekh; Malcolm P MacConmara; Adam C Yopp; Tao Wang; Hao Zhu

doi:10.1016/j.cell.2019.03.026

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease

Cell. 2019 Apr 18;177(3):608-621.e12. doi: 10.1016/j.cell.2019.03.026. Epub 2019 Apr 4.

Authors

Min Zhu¹, Tianshi Lu², Yuemeng Jia¹, Xin Luo³, Purva Gopal⁴, Lin Li¹, Mobolaji Odewole⁵, Veronica Renteria⁵, Amit G Singal⁵, Younghoon Jang⁶, Kai Ge⁶, Sam C Wang⁷, Mahsa Sorouri¹, Justin R Parekh⁸, Malcolm P MacConmara⁸, Adam C Yopp⁸, Tao Wang⁹, Hao Zhu¹⁰

Affiliations

¹ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA, 75390.
³ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ NIDDK, NIH, Bethesda, MD 20892, USA.
⁷ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁸ Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁹ Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA, 75390; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, 75390. Electronic address: [email protected].
¹⁰ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].

Abstract

Normal tissues accumulate genetic changes with age, but it is unknown if somatic mutations promote clonal expansion of non-malignant cells in the setting of chronic degenerative diseases. Exome sequencing of diseased liver samples from 82 patients revealed a complex mutational landscape in cirrhosis. Additional ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. The number and size of mutant clones increased as a function of fibrosis stage and tissue damage. To interrogate the functional impact of mutated genes, a pooled in vivo CRISPR screening approach was established. In agreement with sequencing results, examination of 147 genes again revealed that loss of Pkd1, Kmt2d, and Arid1a promoted clonal expansion. Conditional heterozygous deletion of these genes in mice was also hepatoprotective in injury assays. Pre-malignant somatic alterations are often viewed through the lens of cancer, but we show that mutations can promote regeneration, likely independent of carcinogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Chronic Disease
Clustered Regularly Interspaced Short Palindromic Repeats / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Exome Sequencing
Female
Humans
Hydrolases / deficiency
Hydrolases / genetics
Liver / metabolism*
Liver / pathology
Liver Cirrhosis / chemically induced
Liver Cirrhosis / genetics
Liver Cirrhosis / pathology
Liver Diseases / genetics
Liver Diseases / pathology*
Male
Mice
Mice, Knockout
Middle Aged
Mutation
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Regeneration* / physiology
TRPP Cation Channels / genetics
TRPP Cation Channels / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

ARID1A protein, human
DNA-Binding Proteins
KMT2D protein, human
Neoplasm Proteins
Nuclear Proteins
PPARGC1B protein, human
RNA-Binding Proteins
TRPP Cation Channels
Transcription Factors
polycystic kidney disease 1 protein
Hydrolases
fumarylacetoacetase

Abstract

Publication types

MeSH terms

Substances

Grants and funding