Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers

The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromati...

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Bibliographic Details
Authors: Llorens-Giralt, Palmira, Ruiz-Romero, Marina, Nurtdinov, Ramil, Herranz-Itúrbide, Macarena, Vicent, Guillermo P., Serras, Florenci, Fabregat, Isabel, Corominas, Montserrat
Format: article
Status:Published version
Publication Date:2025
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/421147
Online Access:http://hdl.handle.net/10261/421147
https://api.elsevier.com/content/abstract/scopus_id/105009698765
Access Level:Open access
Keyword:Liver
Regeneration
Chromatin dynamics
Enhancers
Transcription factors
Development
Hepatocyte
ATF3
NRF2
Description
Summary:The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice. We show that the expression of crucial regeneration genes is orchestrated by a diverse array of cis-regulatory elements, including regeneration-specific enhancers and enhancers repurposed from various developmental stages. These enhancers collaborate to activate the transcriptional programs required for hepatocyte priming and proliferation, with their activity initially regulated by the activator protein-1 (AP-1) complex and ATF3, and subsequently by nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) during proliferation. Our results also indicate that hepatic regeneration involves the repression of enhancers regulating liver-specific metabolic functions, particularly those involved in lipid metabolism. This study provides a genome-wide atlas of enhancer-gene interactions, offering new insights into the regulatory mechanisms underlying liver regeneration.

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