The paper is signed by researcher Palmira Llorens-Giralt — first author of the article — and professors Florenci Serras and Montserrat Corominas, all three from the Department of Genetics, Microbiology and Statistics of the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB). Researchers from the Bellvitge Biomedical Research Institute (IDIBELL) and the Area CIBER of Liver and Digestive Diseases (CIBEREHD), the Centre for Genomic Regulation (CRG) and the Institute of Molecular Biology of Barcelona (IBMB-CSIC) have also participated.

The study uses mouse liver after organ resection to analyse 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 tumours 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”, says Montserrat Corominas, who coordinated the study together with Isabel Fabregat, from the IDIBELL.

Similarities with embryonic development of the liver

To obtain a global and dynamic view of the regeneration process, the researchers have analysed multiple genomic data that have allowed them, for example, to compare regeneration with embryonic development of the liver and to detect parallels between the two processes. With this approach, they have observed that the expression of key genes for regeneration is orchestrated by a wide variety of regeneration-responsive regulatory elements, including enhancers — DNA regions that activate gene expression — specific to regeneration, but also reactivated developmental enhancers. That is, re-used enhancers from various stages of embryonic development, with the aim of activating cellular processes essential for the proliferation of hepatocytes, the most abundant cells in the liver.

Researchers have 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 programmes are prioritized while energy-intensive metabolic processes, such as the synthesis of bile acids and retinols, are temporarily inhibited”, says Palmira Llorens-Giralt.

The study also identifies possible transcriptional regulators that orchestrate liver regeneration. At the start of this process, the AP-1 and ATF3 complexes would be responsible for activating the enhancers responsible for turning on transcriptional programmes, i.e. the gene activation sequences necessary for dormant hepatocytes to re-enter the cell and begin to proliferate. In a second phase, this regulation would be dominated by NRF2. These are three transcription factors, i.e. proteins that regulate the activity of genes by activating or repressing their transcription, which is one of the ways in which genes transmit information to direct the functional response of cells.

A bridge to translational regenerative medicine

One of the highlights of this study is to provide a genome-wide map of enhancer-gene interactions. Together with the identification of key regulators in early liver regeneration, this could be a valuable resource for future studies focusing on regulatory elements involved in liver regeneration.

Although this is a basic research study and therefore aims to better understand the fundamental mechanisms of regeneration, with no immediate clinical application, the researchers stress that it may have implications for the development of regenerative medicine. “It is this in-depth knowledge that can lay the groundwork for future medical advances and eventually translate into concrete therapeutic interventions, such as drugs that activate specific enhancers or modulate the regenerative response. Thus, studies like this one can act as a bridge to translational regenerative medicine”, the researchers conclude.