Epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1
Abstract Background Transcriptional co-regulators fine-tune gene expression by modulating transcription factor activity and chromatin dynamics. HCF-1 (Host Cell Factor 1), a conserved transcriptional co-regulator, has been implicated in cell cycle progression, liver metabolism, and regeneration. Los...
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BMC
2025-07-01
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| Online Access: | https://doi.org/10.1186/s12864-025-11786-5 |
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| author | Shruti Kaushal Debashruti Bhattacharya Saran Kumar Winship Herr Jaspreet Kaur Dhanjal Shilpi Minocha |
| author_facet | Shruti Kaushal Debashruti Bhattacharya Saran Kumar Winship Herr Jaspreet Kaur Dhanjal Shilpi Minocha |
| author_sort | Shruti Kaushal |
| collection | DOAJ |
| description | Abstract Background Transcriptional co-regulators fine-tune gene expression by modulating transcription factor activity and chromatin dynamics. HCF-1 (Host Cell Factor 1), a conserved transcriptional co-regulator, has been implicated in cell cycle progression, liver metabolism, and regeneration. Loss of hepatocyte-specific HCF-1 in mice leads to spontaneous NAFLD, which rapidly exacerbates to NASH and compromises liver regeneration. While its role in transcriptional regulation is well-established, the impact of HCF-1 on epigenetic modifications remains relatively unexplored. Methods To investigate the consequences of HCF-1 depletion, we performed histological and biochemical analyses of murine livers, assessing liver injury, lipid accumulation, and hepatocyte proliferation upon 2/3 partial hepatectomy (PH). Additionally, we conducted RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) for H3K4me3 and RNA polymerase II (POL2) to examine the epigenetic and transcriptional alterations associated with HCF-1 loss. Results Loss of HCF-1 results in severe liver injury, causing hallmark features of NAFLD, including steatosis, inflammation, fibrosis, and mitochondrial dysfunction. Following injury, hepatocytes typically re-enter the cell cycle to replenish lost cells. However, in the absence of HCF-1, hepatocytes fail to proliferate leading to a progressive decline in liver function. Even upon 2/3 PH, HCF-1-deficient hepatocytes remain arrested in the cell cycle, further exacerbating disease severity and preventing tissue regeneration. RNA-seq analyses revealed significant downregulation of genes involved in cell cycle progression, metabolism, and mitochondrial structure and function including those regulating oxidative phosphorylation. ChIP-seq data showed altered H3K4me3 patterns at promoter and enhancer regions of key hepatic genes. These findings indicate that HCF-1 is essential for maintaining transcriptional and epigenetic landscapes necessary for hepatocyte proliferation and regeneration. Conclusions Our study establishes HCF-1 as a critical regulator of hepatic homeostasis, with roles extending beyond transcriptional control to epigenetic regulation of liver function and repair. Loss of HCF-1 not only induces liver injury and NAFLD but also prevents hepatocyte proliferation, impairing regeneration and accelerating disease progression. |
| format | Article |
| id | doaj-art-7cb2869f4de44d22b96206ab480bf018 |
| institution | Kabale University |
| issn | 1471-2164 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | BMC Genomics |
| spelling | doaj-art-7cb2869f4de44d22b96206ab480bf0182025-08-20T03:42:37ZengBMCBMC Genomics1471-21642025-07-0126112710.1186/s12864-025-11786-5Epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1Shruti Kaushal0Debashruti Bhattacharya1Saran Kumar2Winship Herr3Jaspreet Kaur Dhanjal4Shilpi Minocha5Department of Computational Biology, Indraprastha Institute of Information Technology (IIITD)Kusuma School of Biological Sciences, Indian Institute of Technology Delhi (IITD)Kusuma School of Biological Sciences, Indian Institute of Technology Delhi (IITD)Centre for Integrative Genomics (CIG), Génopode, University of LausanneDepartment of Computational Biology, Indraprastha Institute of Information Technology (IIITD)Kusuma School of Biological Sciences, Indian Institute of Technology Delhi (IITD)Abstract Background Transcriptional co-regulators fine-tune gene expression by modulating transcription factor activity and chromatin dynamics. HCF-1 (Host Cell Factor 1), a conserved transcriptional co-regulator, has been implicated in cell cycle progression, liver metabolism, and regeneration. Loss of hepatocyte-specific HCF-1 in mice leads to spontaneous NAFLD, which rapidly exacerbates to NASH and compromises liver regeneration. While its role in transcriptional regulation is well-established, the impact of HCF-1 on epigenetic modifications remains relatively unexplored. Methods To investigate the consequences of HCF-1 depletion, we performed histological and biochemical analyses of murine livers, assessing liver injury, lipid accumulation, and hepatocyte proliferation upon 2/3 partial hepatectomy (PH). Additionally, we conducted RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) for H3K4me3 and RNA polymerase II (POL2) to examine the epigenetic and transcriptional alterations associated with HCF-1 loss. Results Loss of HCF-1 results in severe liver injury, causing hallmark features of NAFLD, including steatosis, inflammation, fibrosis, and mitochondrial dysfunction. Following injury, hepatocytes typically re-enter the cell cycle to replenish lost cells. However, in the absence of HCF-1, hepatocytes fail to proliferate leading to a progressive decline in liver function. Even upon 2/3 PH, HCF-1-deficient hepatocytes remain arrested in the cell cycle, further exacerbating disease severity and preventing tissue regeneration. RNA-seq analyses revealed significant downregulation of genes involved in cell cycle progression, metabolism, and mitochondrial structure and function including those regulating oxidative phosphorylation. ChIP-seq data showed altered H3K4me3 patterns at promoter and enhancer regions of key hepatic genes. These findings indicate that HCF-1 is essential for maintaining transcriptional and epigenetic landscapes necessary for hepatocyte proliferation and regeneration. Conclusions Our study establishes HCF-1 as a critical regulator of hepatic homeostasis, with roles extending beyond transcriptional control to epigenetic regulation of liver function and repair. Loss of HCF-1 not only induces liver injury and NAFLD but also prevents hepatocyte proliferation, impairing regeneration and accelerating disease progression.https://doi.org/10.1186/s12864-025-11786-5HCF-1EpigeneticsMethylationChIP-seqNon-alcoholic fatty liver disease |
| spellingShingle | Shruti Kaushal Debashruti Bhattacharya Saran Kumar Winship Herr Jaspreet Kaur Dhanjal Shilpi Minocha Epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1 BMC Genomics HCF-1 Epigenetics Methylation ChIP-seq Non-alcoholic fatty liver disease |
| title | Epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1 |
| title_full | Epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1 |
| title_fullStr | Epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1 |
| title_full_unstemmed | Epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1 |
| title_short | Epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1 |
| title_sort | epigenetic modifications in the murine liver upon depletion of transcriptional coregulator host cell factor 1 |
| topic | HCF-1 Epigenetics Methylation ChIP-seq Non-alcoholic fatty liver disease |
| url | https://doi.org/10.1186/s12864-025-11786-5 |
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