cAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool
- University of Miami, United States
- University of California, San Francisco, United States
- University of California, Berkeley, United States
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.
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Funding
National Institute of Neurological Disorders and Stroke (R21CA191668)
- Gaofeng Wang
National Cancer Institute (R01NS089525)
- Gaofeng Wang
National Institute of General Medical Sciences (GM079465)
- Christopher J Chang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Camarena et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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cAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool
eLife 6:e29750.
https://doi.org/10.7554/eLife.29750
