Faculty, Staff and Student Publications

Language

English

Publication Date

4-27-2023

Journal

Cell

DOI

10.1016/j.cell.2023.03.014

PMID

37040760

PMCID

PMC10321862

PubMedCentral® Posted Date

4-27-2024

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Animals, Humans, Male, Mice, Histone-Lysine N-Methyltransferase, Liver, Metabolic Diseases, Mosaicism, Non-alcoholic Fatty Liver Disease

Published Open-Access

yes

Additional Files
nihms-1884004-f0001.jpg (340 kB)
Graphical Abstract
Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.