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

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)608-621.e12
JournalCell
Volume177
Issue number3
DOIs
StatePublished - Apr 18 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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