Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease

Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu Hsuan Lin, Meng Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Tbx3, Bcl6, or Smyd2 resulted in protection against hepatic steatosis. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.

Original languageEnglish (US)
Pages (from-to)1968-1984.e20
JournalCell
Volume186
Issue number9
DOIs
StatePublished - Apr 27 2023

Keywords

  • Gpam
  • Mboat7
  • NAFLD
  • NASH
  • Smyd2
  • Tbx3
  • chronic liver disease
  • fatty liver disease
  • in vivo screening
  • somatic mosaicism

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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