1. Cell Biology
  2. Chromosomes and Gene Expression
Download icon

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

  1. Vladimir Camarena
  2. David W Sant
  3. Tyler C Huff
  4. Sushimita Mustafi
  5. Ryan K Muir
  6. Allegra T Aron
  7. Christopher J Chang
  8. Adam R Renslo
  9. Paula Monje
  10. Gaofeng Wang  Is a corresponding author
  1. University of Miami, United States
  2. University of California, San Francisco, United States
  3. University of California, Berkeley, United States
Research Article
  • Cited 15
  • Views 1,750
  • Annotations
Cite this article as: eLife 2017;6:e29750 doi: 10.7554/eLife.29750

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.

Article and author information

Author details

  1. Vladimir Camarena

    Department of Human Genetics, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9466-6863
  2. David W Sant

    Department of Human Genetics, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Tyler C Huff

    Department of Human Genetics, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sushimita Mustafi

    Department of Human Genetics, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ryan K Muir

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Allegra T Aron

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Christopher J Chang

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Adam R Renslo

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Paula Monje

    Department of Neurological Surgery, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Gaofeng Wang

    Department of Human Genetics, University of Miami, Miami, United States
    For correspondence
    gwang@med.miami.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8202-8282

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.

Reviewing Editor

  1. Yang Shi, Boston Children's Hospital, United States

Publication history

  1. Received: June 20, 2017
  2. Accepted: December 13, 2017
  3. Accepted Manuscript published: December 14, 2017 (version 1)
  4. Version of Record published: December 27, 2017 (version 2)

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.

Metrics

  • 1,750
    Page views
  • 320
    Downloads
  • 15
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)