ArticleCell2023
Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
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Article in Cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52citing papers in PubMed
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52 citing papers in PubMed, 70 citations in OpenAlex.
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Authors and funding
20 authors at 4 institutions in 2 countries.
Zixi WangChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Shijia ZhuLiver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Yuemeng JiaChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Yunguan WangQuantitative Biomedical Research Center, Department of Population and Data Sciences, Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Naoto KubotaLiver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Naoto FujiwaraLiver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ruth GordilloTouchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cheryl LewisTissue Management Shared Resource, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Min ZhuChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Tripti SharmaChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Lin LiChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Qiyu ZengChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Yu-Hsuan LinChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Meng-Hsiung HsiehChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Purva GopalDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Tao WangQuantitative Biomedical Research Center, Department of Population and Data Sciences, Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Matt HoareUniversity of Cambridge Department of Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; University of Cambridge Early Cancer Institute, Hutchison Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
Peter CampbellCancer Genome Project, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
Yujin HoshidaLiver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Hao ZhuChildren's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hao.zhu@utsouthwestern.edu.
The University of Texas Southwestern Medical Center · USSouthwestern Medical Center · USHutchison/MRC Research Centre · GBWellcome Sanger Institute · GB
Funding
UT Southwestern Medical Center Simmons Comprehensive Cancer CenterP30CA142543 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI MELANIE H. COBB · 2010 to 2026
$53.7MUT Southwestern NORCP30DK127984 · NIDDK · UT SOUTHWESTERN MEDICAL CENTER · PI Jeff G McDonald · 2022 to 2026
$7.4MTrial of Statins for Chemoprevention in Hepatocellular CarcinomaR01CA255621 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI CHUNG, RAYMOND T, HOSHIDA, YUJIN · 2021 to 2025
$3.6MReverse-engineering precision liver cancer chemopreventionR01CA233794 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI HOSHIDA, YUJIN · 2019 to 2023
$3.5MDetermining how chronic ETOH influences the regenerative activities of hepatocyte subpopulationsR01AA028791 · NIAAA · UT SOUTHWESTERN MEDICAL CENTER · PI ZHU, HAO · 2021 to 2025
$2.7MImproving hepatocellular carcinoma mouse modeling by understanding the malignant potential and biology of liver cell subpopulationsR01CA251928 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI ZHU, HAO · 2020 to 2024
$2.7MInvestigating imitation SWI chromatin remodeling complexes in mammalian tissue regenerationR01DK125396 · NIDDK · UT SOUTHWESTERN MEDICAL CENTER · PI ZHU, HAO · 2020 to 2023
$1.5MApplying deep learning to predict T cell receptor binding specificity of neoantigens and response to checkpoint inhibitorsR01CA258584 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI WANG, TAO, WANG, XINLEI · 2021 to 2025
$1.4MCancer Research UK 26813NCI NIH HHS P30 CA142543NCI NIH HHS R01 CA233794NCI NIH HHS R01 CA251928NCI NIH HHS R01 CA255621NCI NIH HHS R01 CA258584NIAAA NIH HHS R01 AA028791NIDDK NIH HHS P30 DK127984NIDDK NIH HHS R01 DK125396
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.
Indexed as
Metabolic DiseasesNon-alcoholic Fatty Liver DiseaseAnimalsHistone-Lysine N-MethyltransferaseHumansLiverMaleMiceMosaicismHistone-Lysine N-MethyltransferaseSMYD2 protein, humanchronic liver diseasefatty liver diseaseGpamin vivo screeningMboat7NAFLDNASHSmyd2somatic mosaicismTbx3
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