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

Llorens-Giralt, Palmira; Ruiz-Romero, Marina; Nurtdinov, Ramil; Herranz-Itúrbide, Macarena; Vicent, Guillermo Pablo; Serras, Florenci; Fabregat, Isabel; Corominas Guiu, Montserrat

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

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dc.contributor.author Llorens-Giralt, Palmira
dc.contributor.author Ruiz-Romero, Marina
dc.contributor.author Nurtdinov, Ramil
dc.contributor.author Herranz-Itúrbide, Macarena
dc.contributor.author Vicent, Guillermo Pablo
dc.contributor.author Serras, Florenci
dc.contributor.author Fabregat, Isabel
dc.contributor.author Corominas Guiu, Montserrat
dc.date.accessioned 2025-10-07T05:36:13Z
dc.date.available 2025-10-07T05:36:13Z
dc.date.issued 2025
dc.description.abstract 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.
dc.description.sponsorship This project was funded by PID2021-123300NB-100 from MCIN/AEI/10.13039/501100011033/FEDER, UE to F.S and M.C.; 2021SGR00293 from the Agency for the Management of University and Research Grants (Generalitat de Catalunya) to M.C.; PID2021-122551OB-100 from MCIN/AEI/10.13039/501100011033/FEDER, UE to I.F.; and FPU20/01473 from the Spanish Ministerio de Universidades to P.L.G. We thank R. Guigó for financial support to M.R.R. and R.N. through grant PID2021-128956NB-I00 funded by MCIN/AEI/10.13039/501100011033/FEDER, UE. M.R.R. and R.N. acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S and MCIN/AEI/10.13039/501100011033) and the Generalitat de Catalunya through the CERCA program.
dc.format.mimetype application/pdf
dc.identifier.citation Llorens-Giralt P, Ruiz-Romero M, Nurtdinov R, Herranz-Itúrbide M, Vicent GP, Serras F, et al. Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers. Cell Genom. 2025 Jul 9;5(7):100887. DOI: 10.1016/j.xgen.2025.100887
dc.identifier.doi http://dx.doi.org/10.1016/j.xgen.2025.100887
dc.identifier.issn 2666-979X
dc.identifier.uri http://hdl.handle.net/10230/71404
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Genom. 2025 Jul 9;5(7):100887
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-123300NB-100
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-122551OB-100
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-128956NB-I00
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword ATF3
dc.subject.keyword NRF2
dc.subject.keyword Chromatin dynamics
dc.subject.keyword Development
dc.subject.keyword Enhancers
dc.subject.keyword Hepatocyte
dc.subject.keyword Liver
dc.subject.keyword Regeneration
dc.subject.keyword Transcription factors
dc.title Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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