ARID1A Gene Knockout Improves Regeneration in Mice

Researchers have made the accidental discovery that removing the gene ARID1A in mice produces greater regenerative capacity. The team was focused on liver cancer research so most of their observations relate to liver regeneration, but they note that the improvement appears in other tissues as well:

The liver is unique among human solid organs in its robust regenerative capability. A healthy liver can regenerate up to 70 percent of its tissue after injury. However, when the liver has been repeatedly damaged - by chemical toxins or chronic disease - it loses its ability to regenerate. Following repeated injuries, cirrhosis or scar tissue forms, greatly increasing the risk of cancer. In humans, the gene ARID1A is mutated in several cancers, including liver cancer, pancreatic cancer, breast cancer, endometrial cancer, and lung cancer. It is not mutated in every type of cancer, but in a significant number. Those mutations are found in 10 to 20 percent of all cancers, and the mutations render the gene inactive.

Based on this association, the researchers hypothesized that mice lacking Arid1a would develop liver damage and, eventually, liver cancer. They were surprised when the opposite proved to be the case - no liver damage occurred. In fact, livers of the mice regenerated faster and appeared to function better. On observation, livers in the mice without the gene appeared healthier. Blood tests confirmed improved liver function. When researchers deleted the gene in mice with various liver injuries, they found that the livers replaced tissue mass quicker and showed reduced fibrosis in response to chemical injury. Also, other tissues such as wounded skin healed faster in Arid1a-deficient mice.

No drugs are currently available to mimic a lack of this protein, although the researchers are searching for one. "We want to identify small molecules that mimic the effect of these genetic findings. The ideal drug would be one that helps the liver heal while inhibiting the development of cancer. That would be the perfect drug for my patients." Loss of the gene and the protein it expresses may accelerate regeneration by reorganizing how genes are packaged in the genome so that the cells can more easily switch back and forth toward a more regenerative state, sort of like a toggle switch.

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2016/march/zhu-liver-regeneration.html

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