Mapping key DNA regions that activate liver regeneration
The genetic mechanisms behind liver regeneration have been revealed, including interplay between regeneration-specific enhancers and reactivated developmental enhancers.
A study led by researchers at the University of Barcelona (Spain) has identified the specific DNA regions responsible for triggering liver regeneration, providing new insights into one of the body’s most remarkable healing processes. The study maps the genome-wide interactions between regulatory elements and key genes involved in liver regeneration.
While the liver’s extraordinary ability to restore its mass and function after injury has long been recognized, the precise genetic mechanisms controlling this process have remained elusive. This research addresses this fundamental gap by identifying the specific DNA elements and transcription factors orchestrating regeneration. The study builds upon previous work by creating a comprehensive map of the non-coding DNA regions that control gene expression during liver regeneration, advancing our understanding beyond the previously identified signaling pathways.
The researchers used mouse liver after organ resection to analyze changes in chromatin, the structure in which DNA is organized within the cell nucleus, which plays a key role in regulating gene expression during regeneration.
“Resection or partial hepatectomy is a common clinical practice, both in the removal of liver tumors and in living donor transplants, where part of the liver is transplanted to a patient with liver dysfunction, so understanding how this process works can help to design strategies that optimize its response,” explained Montserrat Corominas, who coordinated the study together with Isabel Fabregat.
To obtain a global and dynamic view of the regeneration process, the team analyzed multiple genomic data that allowed them to compare regeneration with embryonic development of the liver and detect parallels between the two processes.
From the future of personalized therapies to challenges in pediatric cancer treatments, read about some of the most notable moments.
The study revealed that the expression of key genes for regeneration is orchestrated by a wide variety of regeneration-responsive regulatory element, including two types of enhancers:
- Regeneration-specific enhancers that are uniquely activated during the healing process
- Reactivated developmental enhancers that are repurposed from various stages of embryonic development
These enhancers work together to activate the transcriptional programs required for hepatocyte priming and proliferation, the most abundant cells in the liver.
The researchers also discovered that liver regeneration involves the repression of enhancers that regulate specific metabolic functions of the liver, especially those involved in the metabolism of fats and other lipids.
“This reveals that regeneration is a highly regulated process in which an inverse relationship is established: these proliferation programs are prioritized while energy-intensive metabolic processes, such as the synthesis of bile acids and retinols, are temporarily inhibited,” explained first author Palmira Llorens-Giralt.
The study also identifies the transcription factors that orchestrate liver regeneration. In the initial phase, the AP-1 complex and ATF3 are responsible for activating the enhancers that turn on transcriptional programs necessary for dormant hepatocytes to re-enter the cell cycle and begin to proliferate. In a second phase, this regulation is dominated by NRF2. These three transcription factors regulate gene activity by activating or repressing their transcription, directing the functional response of cells during regeneration.
This research provides a genome-wide map of enhancer-gene interactions along with the identification of key regulators in early liver regeneration, which could be a valuable resource for future studies. These insights could potentially lead to new therapeutic approaches for enhancing liver regeneration or inform strategies for other organs with more limited healing capacities.
