TY - JOUR
T1 - Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease
AU - Zhu, Min
AU - Lu, Tianshi
AU - Jia, Yuemeng
AU - Luo, Xin
AU - Gopal, Purva
AU - Li, Lin
AU - Odewole, Mobolaji
AU - Renteria, Veronica
AU - Singal, Amit G.
AU - Jang, Younghoon
AU - Ge, Kai
AU - Wang, Sam C.
AU - Sorouri, Mahsa
AU - Parekh, Justin R.
AU - MacConmara, Malcolm P.
AU - Yopp, Adam C.
AU - Wang, Tao
AU - Zhu, Hao
N1 - Funding Information:
We would like to thank Helen Hobbs and Teresa Eversole for contributing human samples; Sean Morrison, Joshua Mendell, Branden Tarlow, and Jian Xu for constructive comments on the manuscript; Cheryl Lewis and John Shelton for histopathology; and the CRI Sequencing Core (Jian Xu, Xin Liu) and Admera Health (Yun Zhao) for genomics. T.W. is supported by a R03ES026397-01. T.W. and X.L. were supported by CPRIT ( RP150596 ). H.Z. was supported by the Pollack Foundation , an NIH/NIDDK R01 grant ( DK111588 ), a Burroughs Wellcome Career Award for Medical Scientists , a CPRIT Scholar Award ( R1209 ), a Stand Up To Cancer Innovative Research Grant (SU2C-AACR-IRG 10-16). Stand Up To Cancer is a program of the Entertainment Industry Foundation, and its research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/4/18
Y1 - 2019/4/18
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2019.03.026
DO - 10.1016/j.cell.2019.03.026
M3 - Article
C2 - 30955891
AN - SCOPUS:85064261472
SN - 0092-8674
VL - 177
SP - 608-621.e12
JO - Cell
JF - Cell
IS - 3
ER -