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.

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
  • 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
  • Whole Exome Sequencing

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