As we age, spontaneous mutations in DNA increase and accumulate in normal tissues – leading to diseases such as cancer. Currently the effects of these mutations on organ regeneration is largely unknown. Scientists from the Children's Medical Center Research Institute at UT Southwestern (CRI; TX, USA) have recently published research in Cell describing the effects of common somatic mutations in the liver – and have identified mutations which can promote the regeneration of cells during liver damage.
"Mutations that arise in normal cells are most often viewed through the lens of cancer,” commented Hao Zhu, corresponding author of the paper and Associate Professor at CRI and of Internal Medicine and Pediatrics at UT Southwestern. “While certain mutations can represent steps toward the development of cancer, other mutations may actually promote tissue healing without causing cancer."
In the study, mutated genes in patients with chronic liver disease were identified using a variety of techniques, including novel computational methods. This data was then evaluated to determine the correlation between the mutations and their effects on the liver and cell function.
"Cancer sequencing has been performed for a long time, but normal tissue sequencing is still new to many researchers. Since there is no set method for identifying mutations in normal tissues, we had to develop our own," explained Tao Wang, Assistant Professor of Population and Data Sciences and the Center for the Genetics of Host Defense at UT Southwestern.
Hundreds of mutations in these liver samples were identified in the patients, which were then analyzed in mouse livers through new CRISPR genetic screening methods and allowing for the analysis of the consequences of these mutations on liver regeneration.
"The CRISPR screening method developed by Joyce Jia, a graduate student in my lab, was a critical piece of the study that allowed us to pinpoint important genes among a large number of candidates. Not only has this approach allowed us to examine the impact of somatic mutations found in people, we hope to use it to find new drugs to increase organ regeneration in humans," noted Zhu.
Through this method, several mutations were found which pronounced the effects of liver regeneration - including mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. When these genes were deleted in the mice to mimic the effects of their mutation in human liver samples, increased liver regeneration was observed.
Currently, patients with liver disease have limited treatment options. Additionally, chronic tissue damage, especially in the liver, promotes the development of cancer. It is therefore incredibly important to develop novel treatments for this disease.
"We discovered that many mutations provided liver cells with fitness advantages, giving them an edge over nonmutated cells in terms of growth and survival after environmental insults," Zhu concluded.
Sources: Zhu M, Lu T Jia Y et al. Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease. Cell. doi.org/10.1016/j.cell.2019.03.026 (2019)(Epub ahead of print); https://www.utsouthwestern.edu/newsroom/articles/year-2019/tissue-regeneration.html