TY - JOUR T1 - Oscillatory cAMP signaling rapidly alters H3K4 methylation JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900529 VL - 3 IS - 1 SP - e201900529 AU - Tyler C Huff AU - Vladimir Camarena AU - David W Sant AU - Zachary Wilkes AU - Derek Van Booven AU - Allegra T Aron AU - Ryan K Muir AU - Adam R Renslo AU - Christopher J Chang AU - Paula V Monje AU - Gaofeng Wang Y1 - 2020/01/01 UR - https://www.life-science-alliance.org/content/3/1/e201900529.abstract N2 - Epigenetic variation reflects the impact of a dynamic environment on chromatin. However, it remains elusive how environmental factors influence epigenetic events. Here, we show that G protein–coupled receptors (GPCRs) alter H3K4 methylation via oscillatory intracellular cAMP. Activation of Gs-coupled receptors caused a rapid decrease of H3K4me3 by elevating cAMP, whereas stimulation of Gi-coupled receptors increased H3K4me3 by diminishing cAMP. H3K4me3 gradually recovered towards baseline levels after the removal of GPCR ligands, indicating that H3K4me3 oscillates in tandem with GPCR activation. cAMP increased intracellular labile Fe(II), the cofactor for histone demethylases, through a non-canonical cAMP target—Rap guanine nucleotide exchange factor-2 (RapGEF2), which subsequently enhanced endosome acidification and Fe(II) release from the endosome via vacuolar H+-ATPase assembly. Removing Fe(III) from the media blocked intracellular Fe(II) elevation after stimulation of Gs-coupled receptors. Iron chelators and inhibition of KDM5 demethylases abolished cAMP-mediated H3K4me3 demethylation. Taken together, these results suggest a novel function of cAMP signaling in modulating histone demethylation through labile Fe(II). ER -