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PMID: 30955891 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease.

Cell ·Vol. 177 ·No. 3 ·2019-00-18 ·Pages 608-621.e12

Zhu M, Lu T, Jia Y, Luo X, Gopal P, Li L, Odewole M, Renteria V, Singal AG, Jang Y, Ge K, Wang SC, Sorouri M, Parekh JR, MacConmara MP, Yopp AC, Wang T, Zhu H

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.

MeSH Terms
Animals Chronic Disease Clustered Regularly Interspaced Short Palindromic Repeats/genetics DNA-Binding Proteins/genetics,metabolism Female Humans Hydrolases/deficiency,genetics Liver/metabolism,pathology Liver Cirrhosis/chemically induced,genetics,pathology Liver Diseases/genetics,pathology Male Mice Mice, Knockout Middle Aged Mutation Neoplasm Proteins/genetics,metabolism Nuclear Proteins/genetics,metabolism RNA-Binding Proteins/genetics,metabolism Regeneration/physiology TRPP Cation Channels/genetics,metabolism Transcription Factors/genetics,metabolism Whole Exome Sequencing
Chemicals
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
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Zhu Min
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Lu Tianshi
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA, 75390.
Jia Yuemeng
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Luo Xin
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Gopal Purva
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Li Lin
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Odewole Mobolaji
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Renteria Veronica
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Singal Amit G
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jang Younghoon
NIDDK, NIH, Bethesda, MD 20892, USA.
Ge Kai
NIDDK, NIH, Bethesda, MD 20892, USA.
Wang Sam C
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sorouri Mahsa
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Parekh Justin R
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
MacConmara Malcolm P
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Yopp Adam C
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Wang Tao
Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA, 75390; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, 75390. Electronic address: [email protected].
Zhu Hao
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
References (61)
61 references, click to expand
  1. Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009 Jul 15;25(14):1754-60 PMID: 19451168
  2. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.
    Genome Res. 2010 Sep;20(9):1297-303 PMID: 20644199
  3. Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2.
    Cell Rep. 2016 Nov 1;17(6):1671-1682 PMID: 27806304
  4. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.
    Nat Genet. 1996 Mar;12(3):266-73 PMID: 8589717
  5. The ploidy conveyor of mature hepatocytes as a source of genetic variation.
    Nature. 2010 Oct 7;467(7316):707-10 PMID: 20861837
  6. The histogenesis of regenerative nodules in human liver cirrhosis.
    Hepatology. 2010 Mar;51(3):1017-26 PMID: 20198634
  7. STAR: ultrafast universal RNA-seq aligner.
    Bioinformatics. 2013 Jan 1;29(1):15-21 PMID: 23104886
  8. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
    N Engl J Med. 2014 Dec 25;371(26):2477-87 PMID: 25426838
  9. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features.
    Bioinformatics. 2014 Apr 1;30(7):923-30 PMID: 24227677
  10. Somatic mutant clones colonize the human esophagus with age.
    Science. 2018 Nov 23;362(6417):911-917 PMID: 30337457
  11. Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice.
    Hepatology. 2015 Mar;61(3):1012-23 PMID: 25346535
  12. Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration.
    Cell Stem Cell. 2016 Apr 7;18(4):456-66 PMID: 27044474
  13. Genome-scale CRISPR-Cas9 knockout screening in human cells.
    Science. 2014 Jan 3;343(6166):84-87 PMID: 24336571
  14. Frequent aneuploidy among normal human hepatocytes.
    Gastroenterology. 2012 Jan;142(1):25-8 PMID: 22057114
  15. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.
    Nature. 2011 Nov 09;479(7374):547-51 PMID: 22080947
  16. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples.
    Nat Biotechnol. 2013 Mar;31(3):213-9 PMID: 23396013
  17. Uniformity of liver density and nonheme (storage) iron distribution.
    Arch Pathol Lab Med. 1987 Jun;111(6):549-54 PMID: 3579513
  18. ATHLATES: accurate typing of human leukocyte antigen through exome sequencing.
    Nucleic Acids Res. 2013 Aug;41(14):e142 PMID: 23748956
  19. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis.
    Hepatology. 2014 Dec;60(6):1983-92 PMID: 25123086
  20. Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent β-catenin activation in rodents.
    Hepatology. 2014 Jun;59(6):2309-20 PMID: 24122933
  21. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma.
    Cell. 2017 Jun 15;169(7):1327-1341.e23 PMID: 28622513
  22. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.
    Science. 2015 May 22;348(6237):880-6 PMID: 25999502
  23. Epidemiology and Management of Hepatocellular Carcinoma.
    Gastroenterology. 2019 Jan;156(2):477-491.e1 PMID: 30367835
  24. Polycystic liver and kidney diseases.
    Ann Med. 2005;37(8):546-55 PMID: 16338757
  25. Locating the stem cell niche and tracing hepatocyte lineages in human liver.
    Hepatology. 2009 May;49(5):1655-63 PMID: 19309719
  26. Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer.
    Cell. 2015 Aug 13;162(4):766-79 PMID: 26276631
  27. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.
    Nucleic Acids Res. 2010 Sep;38(16):e164 PMID: 20601685
  28. CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing.
    PLoS Comput Biol. 2016 Apr 21;12(4):e1004873 PMID: 27100738
  29. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications.
    Bioinformatics. 2016 Apr 15;32(8):1220-2 PMID: 26647377
  30. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens.
    Genome Biol. 2014;15(12):554 PMID: 25476604
  31. Aneuploidy as a mechanism for stress-induced liver adaptation.
    J Clin Invest. 2012 Sep;122(9):3307-15 PMID: 22863619
  32. A framework for variation discovery and genotyping using next-generation DNA sequencing data.
    Nat Genet. 2011 May;43(5):491-8 PMID: 21478889
  33. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I.
    Nat Genet. 1995 Aug;10(4):453-60 PMID: 7545495
  34. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.
    Clin Gastroenterol Hepatol. 2012 Dec;10(12):1342-1359.e2 PMID: 23041539
  35. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.
    Nat Commun. 2013;4:2218 PMID: 23887712
  36. Clonal analysis of regenerative nodules in hepatitis C virus-induced liver cirrhosis.
    Gastroenterology. 1994 Dec;107(6):1805-11 PMID: 7958695
  37. Hepatocellular Carcinoma From Epidemiology to Prevention: Translating Knowledge into Practice.
    Clin Gastroenterol Hepatol. 2015 Nov;13(12):2140-51 PMID: 26284591
  38. Liver involvement in early autosomal-dominant polycystic kidney disease.
    Clin Gastroenterol Hepatol. 2015 Jan;13(1):155-64.e6 PMID: 25111236
  39. Gene expression in fixed tissues and outcome in hepatocellular carcinoma.
    N Engl J Med. 2008 Nov 6;359(19):1995-2004 PMID: 18923165
  40. Chronic viral hepatitis: the histology report.
    Dig Liver Dis. 2011 Mar;43 Suppl 4:S331-43 PMID: 21459339
  41. LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets.
    Nucleic Acids Res. 2012 Dec;40(22):11189-201 PMID: 23066108
  42. Population dynamics of normal human blood inferred from somatic mutations.
    Nature. 2018 Sep;561(7724):473-478 PMID: 30185910
  43. An evaluation of copy number variation detection tools for cancer using whole exome sequencing data.
    BMC Bioinformatics. 2017 May 31;18(1):286 PMID: 28569140
  44. Age-related remodelling of oesophageal epithelia by mutated cancer drivers.
    Nature. 2019 Jan;565(7739):312-317 PMID: 30602793
  45. Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasion via the PI3K/GSK-3β/β-catenin pathway in hepatocellular carcinoma.
    Oncotarget. 2016 Feb 2;7(5):5327-41 PMID: 26683365
  46. SpeedSeq: ultra-fast personal genome analysis and interpretation.
    Nat Methods. 2015 Oct;12(10):966-8 PMID: 26258291
  47. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.
    Curr Protoc Bioinformatics. 2013;43:11.10.1-11.10.33 PMID: 25431634
  48. Hepatic peroxisome proliferator-activated receptor γ coactivator 1β drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression in mice.
    Hepatology. 2018 Mar;67(3):884-898 PMID: 28857232
  49. Clonality of nodular lesions in liver cirrhosis and chromosomal abnormalities in monoclonal nodules of altered hepatocytes.
    Histopathology. 2010 Apr;56(5):589-99 PMID: 20459569
  50. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues.
    Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13409-14 PMID: 25197050
  51. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing.
    Genome Res. 2012 Mar;22(3):568-76 PMID: 22300766
  52. Clonal analysis of macronodules in cirrhosis.
    Hepatology. 1998 Oct;28(4):953-8 PMID: 9755231
  53. Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver.
    Nature. 2015 Aug 13;524(7564):180-5 PMID: 26245375
  54. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury.
    Nature. 2018 Apr;556(7700):244-248 PMID: 29618815
  55. Age-related clonal hematopoiesis associated with adverse outcomes.
    N Engl J Med. 2014 Dec 25;371(26):2488-98 PMID: 25426837
  56. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs.
    Bioinformatics. 2012 Jul 15;28(14):1811-7 PMID: 22581179
  57. Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma.
    Gastroenterology. 2014 Jan;146(1):222-32.e35 PMID: 24055508
  58. A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo.
    J Am Soc Nephrol. 2004 Dec;15(12):3035-43 PMID: 15579506
  59. Shimmer: detection of genetic alterations in tumors using next-generation sequence data.
    Bioinformatics. 2013 Jun 15;29(12):1498-503 PMID: 23620360
  60. Phosphatase and tensin homolog (PTEN) regulates hepatic lipogenesis, microsomal triglyceride transfer protein, and the secretion of apolipoprotein B-containing lipoproteins.
    Hepatology. 2008 Dec;48(6):1799-809 PMID: 19026012
  61. Liver biopsy assessment in chronic hepatitis.
    Arch Med Res. 2007 Aug;38(6):634-43 PMID: 17613355
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2019.03.026
Email
[email protected]
[email protected]
Published
2019-00-18
Epub
2019-00-04
Pages
608-621.e12
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC6519461
Subset
IM
Grants
NCI NIH HHS · K08 CA222611 · United States
NCI NIH HHS · R01 CA190525 · United States
NIDDK NIH HHS · R01 DK111588 · United States
NIEHS NIH HHS · R03 ES026397 · United States
Corrections
CommentIn
PMID: 31019267
CommentIn
PMID: 31151757
CommentIn
PMID: 32034958
External Links
PubMed source DOI: 10.1016/j.cell.2019.03.026 PMC Full Text View journal details
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