A new study published in Cell has used deep sequencing to offer insights into the mutational landscape of human chronic liver disease, identifying recurrent mutations. Moreover, in vivo CRISPR–Cas9 screening in a mouse model validated the functional relevance of these somatic mutations, demonstrating roles in hepatocyte fitness and liver regeneration.
“It is now clear that normal tissues such as blood, skin and oesophagus harbour a large number of somatic mutations, something previously thought to be more exclusive to cancer,” explains author Hao Zhu. “In the setting of chronically diseased livers, we identified a broad range of recurrent mutations, many of which were in genes not known to be involved in cancer,” he says, adding that there was a knowledge gap in the field as to whether mutations in normal cells within solid organs are functional and can alter cellular physiology or regeneration.
Zhu and colleagues performed whole-exome sequencing of liver samples from 82 individuals (one normal liver sample, with the remainder from patients with chronic liver disease including cirrhosis). Author Tao Wang’s team led the bioinformatics analyses, which revealed a complex mutational landscape with extensive mutational burden and heterogeneity. Further ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D and ARID1A in diseased livers. Notably, the number and volume of clones carrying mutations increased as a function of fibrosis stage and level of liver damage.
To further examine the functional relevance of these mutated genes, the researchers established an in vivo CRISPR–Cas9 screen of 147 genes in Fah-knockout mice, which acted as a model of liver damage and regeneration in the context of chronic disease. Crucially, this screen validated the functional relevance of Pkd1, Kmt2d and Arid1a. Conditional deletion of these genes from hepatocytes in various floxed mice confirmed their role in promoting hepatocyte fitness or liver regeneration in liver injury assays.
The researchers hope their conclusions might be explored in other tissues to determine whether they also harbour mutations that are adaptive rather than maladaptive, and they hope to further develop their screens in the liver to identify potential novel therapeutic targets.
Zhu, M. et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease. Cell 177, 608–621.e12 (2019)
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Ray, K. Mutational landscape in liver disease — fit for regeneration?. Nat Rev Gastroenterol Hepatol 16, 326–327 (2019). https://doi.org/10.1038/s41575-019-0151-9