Oscillatory cAMP signaling rapidly alters H3K4 methylation

Tyler C. Huff, Vladimir Camarena, David W. Sant, Zachary Wilkes, Derek van Booven, Allegra T. Aron, Ryan K. Muir, Adam R. Renslo, Christopher J. Chang, Paula V. Monje, Gaofeng Wang

Research output: Contribution to journalArticle

Abstract

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).

Original languageEnglish (US)
Article numbere201900529
JournalLife Science Alliance
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2020

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Methylation
Endosomes
methylation
Epigenomics
ligand
acidification
environmental factor
Histone Demethylases
Chemical activation
Vacuolar Proton-Translocating ATPases
Guanine Nucleotide Exchange Factors
iron
receptors
Acidification
Chelating Agents
Histones
Chromatin
endosomes
Iron
Ligands

ASJC Scopus subject areas

  • Ecology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Health, Toxicology and Mutagenesis

Cite this

Huff, T. C., Camarena, V., Sant, D. W., Wilkes, Z., van Booven, D., Aron, A. T., ... Wang, G. (2020). Oscillatory cAMP signaling rapidly alters H3K4 methylation. Life Science Alliance, 3(1), [e201900529]. https://doi.org/10.26508/lsa.201900529

Oscillatory cAMP signaling rapidly alters H3K4 methylation. / Huff, Tyler C.; Camarena, Vladimir; Sant, David W.; Wilkes, Zachary; van Booven, Derek; Aron, Allegra T.; Muir, Ryan K.; Renslo, Adam R.; Chang, Christopher J.; Monje, Paula V.; Wang, Gaofeng.

In: Life Science Alliance, Vol. 3, No. 1, e201900529, 01.01.2020.

Research output: Contribution to journalArticle

Huff, TC, Camarena, V, Sant, DW, Wilkes, Z, van Booven, D, Aron, AT, Muir, RK, Renslo, AR, Chang, CJ, Monje, PV & Wang, G 2020, 'Oscillatory cAMP signaling rapidly alters H3K4 methylation', Life Science Alliance, vol. 3, no. 1, e201900529. https://doi.org/10.26508/lsa.201900529
Huff TC, Camarena V, Sant DW, Wilkes Z, van Booven D, Aron AT et al. Oscillatory cAMP signaling rapidly alters H3K4 methylation. Life Science Alliance. 2020 Jan 1;3(1). e201900529. https://doi.org/10.26508/lsa.201900529
Huff, Tyler C. ; Camarena, Vladimir ; Sant, David W. ; Wilkes, Zachary ; van Booven, Derek ; Aron, Allegra T. ; Muir, Ryan K. ; Renslo, Adam R. ; Chang, Christopher J. ; Monje, Paula V. ; Wang, Gaofeng. / Oscillatory cAMP signaling rapidly alters H3K4 methylation. In: Life Science Alliance. 2020 ; Vol. 3, No. 1.
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