Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration
Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathophysiological mechanisms remain elusive. It is a progressive disease, encompassing hepatic steatosis, steatohepatitis with (out) fibrosis, and ultimat...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
|
| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13148-025-01945-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849333176916246528 |
|---|---|
| author | Evelien Van Dijck Steven Van Laere Emilie Logie Steven Timmermans Erik Fransen Joe Ibrahim Timothy J. Kendall Jonathan A. Fallowfield Ligia M. Mateiu Claude Libert Guy Van Camp An Verrijken Luc Van Gaal Sven Francque Wim Van Hul Wim Vanden Berghe |
| author_facet | Evelien Van Dijck Steven Van Laere Emilie Logie Steven Timmermans Erik Fransen Joe Ibrahim Timothy J. Kendall Jonathan A. Fallowfield Ligia M. Mateiu Claude Libert Guy Van Camp An Verrijken Luc Van Gaal Sven Francque Wim Van Hul Wim Vanden Berghe |
| author_sort | Evelien Van Dijck |
| collection | DOAJ |
| description | Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathophysiological mechanisms remain elusive. It is a progressive disease, encompassing hepatic steatosis, steatohepatitis with (out) fibrosis, and ultimately cirrhosis and hepatocellular carcinoma. DNA methylation (DNAm) is dysregulated in MASLD and may play a central role in its pathogenesis. Additionally, aging is associated with MASLD and shares common processes of chronic inflammation and oxidative stress. Therefore, this study focuses on DNAm changes in relation to MASLD progression and epigenetic age acceleration (EAA). Results Liver biopsies from 22 individuals with varying MASLD status were analyzed using Infinium MethylationEPIC BeadChip arrays. Strikingly, progression of MASLD was characterized by gradual DNAm changes, revealing multiple associated KEGG pathways. Additionally, Horvath’s EAA significantly correlated with MASLD stage and individual histological MASLD parameters while LiverClock’s EAA correlated only with MASLD stage. In contrast, both Horvath’s intrinsic EAA and HepClock’s EAA showed no significant correlations. Integrative analyses, leveraging both gradual MASLD and Horvath’s EAA DNAm signatures, gene expression (n = 118), and a MASLD-specific transcriptional regulatory network, identified (regulon-specific) transcription factors implicated in MASLD and EAA progression, representing a transcription factor-network of redox (ferroptosis), immune, and metabolic/endocrine related epigenetic processes. Conclusion Gradual DNAm changes were found to align with progression of MASLD and EAA, with EAA a potential nonbiased quantitative biomarker for MASLD. Integrative analysis highlighted potential new therapeutic transcription factor targets, with special emphasis on AEBP1 and emerging nuclear receptors including CAR(NR1I3), MR(NR3C2), GR(NR3C1), and ESRRG, underscoring the potential of epigenetic redox-metabolic therapies for MASLD. Graphical abstract |
| format | Article |
| id | doaj-art-572f4a3e8a884c2ba95d15f663fb1ded |
| institution | Kabale University |
| issn | 1868-7083 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj-art-572f4a3e8a884c2ba95d15f663fb1ded2025-08-20T03:45:57ZengBMCClinical Epigenetics1868-70832025-08-0117112210.1186/s13148-025-01945-6Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age accelerationEvelien Van Dijck0Steven Van Laere1Emilie Logie2Steven Timmermans3Erik Fransen4Joe Ibrahim5Timothy J. Kendall6Jonathan A. Fallowfield7Ligia M. Mateiu8Claude Libert9Guy Van Camp10An Verrijken11Luc Van Gaal12Sven Francque13Wim Van Hul14Wim Vanden Berghe15Cell Death Signaling–Epigenetics Lab, Department Biomedical Sciences, University of AntwerpCenter for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of AntwerpCell Death Signaling–Epigenetics Lab, Department Biomedical Sciences, University of AntwerpCenter for Inflammation Research, Vlaams Instituut Voor Biotechnologie (VIB)Centre of Medical Genetics, University of AntwerpCentre of Medical Genetics, University of AntwerpCentre for Inflammation Research, Institute for Regeneration and Repair, University of EdinburghCentre for Inflammation Research, Institute for Regeneration and Repair, University of EdinburghCentre of Medical Genetics, University of AntwerpCenter for Inflammation Research, Vlaams Instituut Voor Biotechnologie (VIB)Centre of Medical Genetics, University of AntwerpDepartment of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University HospitalDepartment of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University HospitalDepartment of Gastroenterology and Hepatology, Antwerp University HospitalCentre of Medical Genetics, University of AntwerpCell Death Signaling–Epigenetics Lab, Department Biomedical Sciences, University of AntwerpAbstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathophysiological mechanisms remain elusive. It is a progressive disease, encompassing hepatic steatosis, steatohepatitis with (out) fibrosis, and ultimately cirrhosis and hepatocellular carcinoma. DNA methylation (DNAm) is dysregulated in MASLD and may play a central role in its pathogenesis. Additionally, aging is associated with MASLD and shares common processes of chronic inflammation and oxidative stress. Therefore, this study focuses on DNAm changes in relation to MASLD progression and epigenetic age acceleration (EAA). Results Liver biopsies from 22 individuals with varying MASLD status were analyzed using Infinium MethylationEPIC BeadChip arrays. Strikingly, progression of MASLD was characterized by gradual DNAm changes, revealing multiple associated KEGG pathways. Additionally, Horvath’s EAA significantly correlated with MASLD stage and individual histological MASLD parameters while LiverClock’s EAA correlated only with MASLD stage. In contrast, both Horvath’s intrinsic EAA and HepClock’s EAA showed no significant correlations. Integrative analyses, leveraging both gradual MASLD and Horvath’s EAA DNAm signatures, gene expression (n = 118), and a MASLD-specific transcriptional regulatory network, identified (regulon-specific) transcription factors implicated in MASLD and EAA progression, representing a transcription factor-network of redox (ferroptosis), immune, and metabolic/endocrine related epigenetic processes. Conclusion Gradual DNAm changes were found to align with progression of MASLD and EAA, with EAA a potential nonbiased quantitative biomarker for MASLD. Integrative analysis highlighted potential new therapeutic transcription factor targets, with special emphasis on AEBP1 and emerging nuclear receptors including CAR(NR1I3), MR(NR3C2), GR(NR3C1), and ESRRG, underscoring the potential of epigenetic redox-metabolic therapies for MASLD. Graphical abstracthttps://doi.org/10.1186/s13148-025-01945-6MASLDEpigeneticsDNA methylationEpigenetic ageEpigenetic age accelerationTranscription factor |
| spellingShingle | Evelien Van Dijck Steven Van Laere Emilie Logie Steven Timmermans Erik Fransen Joe Ibrahim Timothy J. Kendall Jonathan A. Fallowfield Ligia M. Mateiu Claude Libert Guy Van Camp An Verrijken Luc Van Gaal Sven Francque Wim Van Hul Wim Vanden Berghe Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration Clinical Epigenetics MASLD Epigenetics DNA methylation Epigenetic age Epigenetic age acceleration Transcription factor |
| title | Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration |
| title_full | Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration |
| title_fullStr | Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration |
| title_full_unstemmed | Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration |
| title_short | Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration |
| title_sort | gradual dna methylation changes reveal transcription factors implicated in metabolic dysfunction associated steatotic liver disease progression and epigenetic age acceleration |
| topic | MASLD Epigenetics DNA methylation Epigenetic age Epigenetic age acceleration Transcription factor |
| url | https://doi.org/10.1186/s13148-025-01945-6 |
| work_keys_str_mv | AT evelienvandijck gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT stevenvanlaere gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT emilielogie gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT steventimmermans gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT erikfransen gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT joeibrahim gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT timothyjkendall gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT jonathanafallowfield gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT ligiammateiu gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT claudelibert gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT guyvancamp gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT anverrijken gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT lucvangaal gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT svenfrancque gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT wimvanhul gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration AT wimvandenberghe gradualdnamethylationchangesrevealtranscriptionfactorsimplicatedinmetabolicdysfunctionassociatedsteatoticliverdiseaseprogressionandepigeneticageacceleration |