TY - JOUR TI - cAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool AU - Camarena, Vladimir AU - Sant, David W AU - Huff, Tyler C AU - Mustafi, Sushmita AU - Muir, Ryan K AU - Aron, Allegra T AU - Chang, Christopher J AU - Renslo, Adam R AU - Monje, Paula V AU - Wang, Gaofeng A2 - Shi, Yang VL - 6 PY - 2017 DA - 2017/12/14 SP - e29750 C1 - eLife 2017;6:e29750 DO - 10.7554/eLife.29750 UR - https://doi.org/10.7554/eLife.29750 AB - 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. KW - cAMP KW - labile Fe(II) KW - 5-hydroxymethylcytosine KW - GPCR KW - RapGEF2 KW - PKA JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -