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

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

Author information

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: Tao.Wang@utsouthwestern.edu.
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: Hao.Zhu@utsouthwestern.edu.

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.

PMID:
30955891
DOI:
10.1016/j.cell.2019.03.026

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