Alterations of Epigenetic Signatures in Hepatocyte Nuclear Factor 4α Deficient Mouse Liver Determined by Improved ChIP-qPCR and (h)MeDIP-qPCR Assays
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Hepatocyte nuclear factor 4α (HNF4α) is a liver-enriched transcription factor essential for liver development and function. In hepatocytes, HNF4α regulates a large number of genes important for nutrient/xenobiotic metabolism and cell differentiation and proliferation. Currently, little is known about the epigenetic mechanism of gene regulation by HNF4α. In this study, the global and specific alterations at the selected gene loci of representative histone modifications and DNA methylations were investigated in Hnf4a-deficient female mouse livers using the improved MeDIP-, hMeDIP- and ChIP-qPCR assay. Hnf4a deficiency significantly increased hepatic total IPed DNA fragments for histone H3 lysine-4 dimethylation (H3K4me2), H3K4me3, H3K9me2, H3K27me3 and H3K4 acetylation, but not for H3K9me3, 5-methylcytosine,or 5-hydroxymethylcytosine. At specific gene loci, the relative enrichments of histone and DNA modifications were changed to different degree in Hnf4a-deficient mouse liver. Among the epigenetic signatures investigated, changes in H3K4me3 correlated the best with mRNA expression. Additionally, Hnf4a-deficient livers had increased mRNA expression of histone H1.2 and H3.3 as well as epigenetic modifiers Dnmt1, Tet3, Setd7, Kmt2c, Ehmt2, and Ezh2. In conclusion, the present study provides convenient improved (h)MeDIP- and ChIP-qPCR assays for epigenetic study. Hnf4a deficiency in young-adult mouse liver markedly alters histone methylation and acetylation, with fewer effects on DNA methylation and 5-hydroxymethylation. The underlying mechanism may be the induction of epigenetic enzymes responsible for the addition/removal of the epigenetic signatures, and/or the loss of HNF4α per se as a key coordinator for epigenetic modifiers.
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A recent study showed that HNF4A loss can impact global 5mC and 5hmC to a small extent.
“A recent study showed that HNF4A loss can impact global 5mC and 5hmC to a small extent (44).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [44]
The Results section on DNA methylation and 5-hydroxymethylation (page unavailable) reports no significant difference in total immunoprecipitated DNA fragments between Hnf4a-deficient and wild-type livers. The Discussion explicitly says Hnf4a deficiency does not cause global changes in DNA methylation or 5-hydroxymethylation; it finds changes at specific gene loci instead. (LLM, conf=0.90)
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- Authors
- Zhang, Q., Lei, X., & Lu, H.
- Affiliations
- SUNY Upstate Medical University (US)
- ORCID
- Zhang, Qinghao
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-01-10
- Volume
- 9
- Issue
- 1
- Pages
- e84925
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3888413
- OpenAlex
- W2058211893
- Cited by
- 16
- References
- 48
- Citations by year
- 2025: 1 · 2021: 1 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 4
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (CA143656, CA159350)
- National Cancer Institute (R03CA143656, CA159350, CA143656, R03CA159350)
- National Institute of Environmental Health Sciences (ES-019487, R01ES019487)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- HNF4α, histone modifications, DNA methylation, 5-hydroxymethylation, histone H3 lysine methylation, histone acetylation, H3K4me3, H3K27me3, H3K9me2, epigenetic regulators, histone H1.2, histone H3.3, transcriptional regulation, ChIP-qPCR, liver development
- MeSH terms
- Animals, Female, Histones, Liver, RNA, Messenger, Sensitivity and Specificity, Reproducibility of Results, Mice, Knockout, DNA Methylation, Epigenesis, Genetic, Chromatin Immunoprecipitation, Mice, Hepatocyte Nuclear Factor 4, Epigenomics, Real-Time Polymerase Chain Reaction
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