Researchers use epigenetic mechanism to regenerate mammalian liver.


Tails in lizards and arms in starfish show an astounding ability to regrow, however, mammals have partially lost the capacity to extensively regenerate body parts. The liver is unique among human solid organs in its robust regenerative capability, with a healthy liver able to regenerate up to 70% of its tissue after injury.  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.  Also, it is unclear if epigenetic mechanisms enforcing tissue differentiation limit mammalian regeneration.  Now, a study led by researchers at UT Southwestern shows that deactivation of a certain protein-coding gene, known as Arid1a, promotes liver tissue regeneration in mammals.  The team states that their research provides new insight into ways to treat liver damage or chronic liver disease. The opensource study is published in the journal Cell Stem Cell.

Previous studies show that in humans, the gene ARID1A is mutated in several cancers.  It has been shown that ARID1A is not mutated in every type of cancer, but in a significant number, with the mutations present in 10 to 20% of all cancers, rendering the gene inactive.  Based on this association, the researchers hypothesized that mice lacking Arid1a would develop liver damage and, eventually, liver cancer. The current study shows that mice lacking Arid1a had no liver damage, with livers of the mice regenerating faster and appearing to function better.

The current study shows that Arid1a is suppressed during liver regeneration and wound healing and that complete deletion in mice leads to improved regeneration.  Results show that the livers were resistant to tissue damage and healed better.  Data findings show that on observation, livers in the mice without the gene appeared healthier with blood tests confirming improved liver function.

Results show that when the lab deleted the gene in mice with various liver injuries, the livers replaced tissue mass quicker and showed reduced fibrosis in response to chemical injury. The group note that other tissues such as wounded skin also healed faster in Arid1a-deficient mice.

The team surmise that their findings show epigenetic reprogramming mediated by deletion of a single gene improves mammalian regeneration and suggests new strategies to promote tissue repair after injury.  They go on to add that their study opens up new areas on how to rejuvenate tissues without necessarily increasing cancer risk.  For the future, the researchers state that they now want to identify small molecules that mimic the effect of these genetic findings. They conclude that the ideal drug would be one that helps the liver heal while inhibiting the development of cancer.

Source: UT Southwestern

 

Mammals have partially lost the extensive regenerative capabilities of some vertebrates, possibly as a result of chromatin-remodeling mechanisms that enforce terminal differentiation. Here, we show that deleting the SWI/SNF component Arid1a substantially improves mammalian regeneration. Arid1a expression is suppressed in regenerating tissues, and genetic deletion of Arid1a increases tissue repair following an array of injuries. Arid1a deficiency in the liver increases proliferation, reduces tissue damage and fibrosis, and improves organ function following surgical resection and chemical injuries. Hepatocyte-specific deletion is also sufficient to increase proliferation and regeneration without excessive overgrowth, and global Arid1a disruption potentiates soft tissue healing in the ear. We show that Arid1a loss reprograms chromatin to restrict promoter access by transcription factors such as C/ebpα, which enforces differentiation, and E2F4, which suppresses cell-cycle re-entry. Thus, epigenetic reprogramming mediated by deletion of a single gene improves mammalian regeneration and suggests strategies to promote tissue repair after injury.  Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration.  Sun et al 2016.

Mammals have partially lost the extensive regenerative capabilities of some vertebrates, possibly as a result of chromatin-remodeling mechanisms that enforce terminal differentiation. Here, we show that deleting the SWI/SNF component Arid1a substantially improves mammalian regeneration. Arid1a expression is suppressed in regenerating tissues, and genetic deletion of Arid1a increases tissue repair following an array of injuries. Arid1a deficiency in the liver increases proliferation, reduces tissue damage and fibrosis, and improves organ function following surgical resection and chemical injuries. Hepatocyte-specific deletion is also sufficient to increase proliferation and regeneration without excessive overgrowth, and global Arid1a disruption potentiates soft tissue healing in the ear. We show that Arid1a loss reprograms chromatin to restrict promoter access by transcription factors such as C/ebpα, which enforces differentiation, and E2F4, which suppresses cell-cycle re-entry. Thus, epigenetic reprogramming mediated by deletion of a single gene improves mammalian regeneration and suggests strategies to promote tissue repair after injury. Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration. Sun et al 2016.

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