PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine
Open accessAbstract
Recent studies have shown that DNA demethylation goes through the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by Tet proteins. However, it is still unclear how the target regions for demethylation are distinguished within their genomic context. Here we show that the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) has the ability to direct local demethylation around its binding sites, the PPAR response elements (PPREs), during adipocyte differentiation. PPARγ is a key regulator of the differentiation process that forms a PPARγ co-activator complex on PPREs and activates the expression of adipocyte-specific genes. The complex is poly(ADP-ribosyl)ated (PARylated) on PPREs, and Tet proteins catalyse the conversion of 5mC to 5hmC locally by their ability to bind to the PAR polymer, thereby inducing region-specific demethylation. Our study demonstrates that a sequence-dependent transcription factor complex can, through its post-translational modification, serve for Tet proteins as a landmark to identify sites of DNA demethylation.
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Recent reports have identified TFs that interact with TET proteins to maintain low 5mC and high 5hmC at enhancers.
“Recent reports have identified TFs that interact with TET proteins to maintain low 5mC and high 5hmC at enhancers (23, 24).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [23]
The section on Tet-mediated hydroxylation reports that PPARγ associates with Tet1 and promotes demethylation and 5hmC production around PPREs; the Discussion identifies the Plin1 PPRE as an adipogenic enhancer. But the paper describes a transient rise in 5hmC during differentiation, followed by a decline, rather than maintenance of high 5hmC at enhancers. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPPARγ recruits TET1, resulting in reduced methylation around its binding sites.
“the nuclear receptor PPARγ (peroxisome proliferator-activated receptor-γ) recruits TET1, resulting in a reduced methylation level around its binding sites through the interaction with TET1 (REF. 85).”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [85]
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“(22) Recent reports have identified TFs that interact with TET proteins to maintain low 5mC and high 5hmC at enhancers.(23,24) Studies transducing a combination of TFs into human fibroblasts to produce highly functional hepatocytes support HNF4A’s involvement in chromatin remodelling.”
BackgroundLecoutre, S., Oger, F., Pourpe, C., Butruille, L., Marousez, L., Dickes-Coopman, A., Laborie, C., Guinez, C., Lesage, J., Vieau, D., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.05.010 · Cited by 49 · see citing works
- Authors
- Fujiki, K., Shinoda, A., Kano, F., Sato, R., Shirahige, K., & Murata, M.
- Affiliations
- The University of Tokyo (JP)
- Corresponding author
- Murata, Masayuki
- Venue
- Nature Communications
- Published
- 2013-08-05
- Volume
- 4
- Issue
- 1
- Pages
- 2262-2262
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2026344296
- Cited by
- 123
- References
- 37
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 4 · 2022: 12 · 2021: 8 · 2020: 12 · 2019: 14 · 2018: 9 · 2017: 17 · 2016: 13 · 2015: 6 · 2014: 8 · 2013: 1
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Tokyo Tech Research Repository (Tokyo Institute of Technology) (submittedVersion)
- Funders
- Kanagawa Academy of Science and Technology
- Japan Society for the Promotion of Science (13J07144, 23657124, 23657001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- PPARγ, poly(ADP-ribosyl)ation, DNA demethylation, 5-hydroxymethylcytosine, TET enzymes, PPAR response element, adipogenesis, post-translational modification, epigenetic regulation, 5-methylcytosine
- MeSH terms
- Adipose Tissue, Amino Acid Sequence, Animals, Base Sequence, Cell Differentiation, Cytosine, DNA-Binding Proteins, Enhancer Elements, Genetic, Humans, Hydroxylation, Molecular Sequence Data, Phenanthrenes, Poly Adenosine Diphosphate Ribose, Protein Binding, Proto-Oncogene Proteins, Adipocytes, DNA Methylation, Response Elements, 3T3-L1 Cells, 5-Methylcytosine, PPAR gamma, Mice, HEK293 Cells
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