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Epigenetics Chromatin. 2017 Jul 12;10:36. doi: 10.1186/s13072-017-0143-3. eCollection 2017.

Vitamin C induces specific demethylation of H3K9me2 in mouse embryonic stem cells via Kdm3a/b.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA USA.
2
Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.
3
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC Canada.
4
Novartis Institutes for Biomedical Research, Cambridge, MA USA.
5
Department of Microbiology and Immunology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC Canada.

Abstract

BACKGROUND:

Histone methylation patterns regulate gene expression and are highly dynamic during development. The erasure of histone methylation is carried out by histone demethylase enzymes. We had previously shown that vitamin C enhances the activity of Tet enzymes in embryonic stem (ES) cells, leading to DNA demethylation and activation of germline genes.

RESULTS:

We report here that vitamin C induces a remarkably specific demethylation of histone H3 lysine 9 dimethylation (H3K9me2) in naïve ES cells. Vitamin C treatment reduces global levels of H3K9me2, but not other histone methylation marks analyzed, as measured by western blot, immunofluorescence and mass spectrometry. Vitamin C leads to widespread loss of H3K9me2 at large chromosomal domains as well as gene promoters and repeat elements. Vitamin C-induced loss of H3K9me2 occurs rapidly within 24 h and is reversible. Importantly, we found that the histone demethylases Kdm3a and Kdm3b are required for vitamin C-induced demethylation of H3K9me2. Moreover, we show that vitamin C-induced Kdm3a/b-mediated H3K9me2 demethylation and Tet-mediated DNA demethylation are independent processes at specific loci. Lastly, we document Kdm3a/b are partially required for the upregulation of germline genes by vitamin C.

CONCLUSIONS:

These results reveal a specific role for vitamin C in histone demethylation in ES cells and document that DNA methylation and H3K9me2 cooperate to silence germline genes in pluripotent cells.

KEYWORDS:

Embryonic stem cells; Epigenetics; Histone lysine demethylase; Histone methylation; Vitamin C

PMID:
28706564
PMCID:
PMC5506665
DOI:
10.1186/s13072-017-0143-3
[Indexed for MEDLINE]
Free PMC Article

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