CAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool

Vladimir Camarena, David W. Sant, Tyler C. Huff, Sushmita Mustafi, Ryan K. Muir, Allegra T. Aron, Christopher J. Chang, Adam R. Renslo, Paula V Monje, Gaofeng Wang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

It is widely accepted that cAMP regulates gene transcription principally by activating the protein kinase A (PKA)-targeted transcription factors. Here, we show that cAMP enhances the generation of 5-hydroxymethylcytosine (5hmC) in multiple cell types. 5hmC is converted from 5- methylcytosine (5mC) by Tet methylcytosine dioxygenases, for which Fe(II) is an essential cofactor. The promotion of 5hmC was mediated by a prompt increase of the intracellular labile Fe(II) pool (LIP). cAMP enhanced the acidification of endosomes for Fe(II) release to the LIP likely through RapGEF2. The effect of cAMP on Fe(II) and 5hmC was confirmed by adenylate cyclase activators, phosphodiesterase inhibitors, and most notably by stimulation of G protein-coupled receptors (GPCR). The transcriptomic changes caused by cAMP occurred in concert with 5hmC elevation in differentially transcribed genes. Collectively, these data show a previously unrecognized regulation of gene transcription by GPCR-cAMP signaling through augmentation of the intracellular labile Fe (II) pool and DNA hydroxymethylation.

Original languageEnglish (US)
Article numbere29750
JournaleLife
Volume6
DOIs
StatePublished - Dec 14 2017

Fingerprint

Iron
DNA
Genes
Transcription
G-Protein-Coupled Receptors
5-Methylcytosine
Dioxygenases
Phosphodiesterase Inhibitors
Acidification
Endosomes
Cyclic AMP-Dependent Protein Kinases
Adenylyl Cyclases
Transcription Factors
5-hydroxymethylcytosine

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

CAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool. / Camarena, Vladimir; Sant, David W.; Huff, Tyler C.; Mustafi, Sushmita; Muir, Ryan K.; Aron, Allegra T.; Chang, Christopher J.; Renslo, Adam R.; Monje, Paula V; Wang, Gaofeng.

In: eLife, Vol. 6, e29750, 14.12.2017.

Research output: Contribution to journalArticle

Camarena, V, Sant, DW, Huff, TC, Mustafi, S, Muir, RK, Aron, AT, Chang, CJ, Renslo, AR, Monje, PV & Wang, G 2017, 'CAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool', eLife, vol. 6, e29750. https://doi.org/10.7554/eLife.29750
Camarena, Vladimir ; Sant, David W. ; Huff, Tyler C. ; Mustafi, Sushmita ; Muir, Ryan K. ; Aron, Allegra T. ; Chang, Christopher J. ; Renslo, Adam R. ; Monje, Paula V ; Wang, Gaofeng. / CAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool. In: eLife. 2017 ; Vol. 6.
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