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

doi:10.26508/lsa.201900529

Title: Oscillatory cAMP signaling rapidly alters H3K4 methylation

Journal Article · 27 December 2019 · Life Science Alliance

DOI: https://doi.org/10.26508/lsa.201900529 · OSTI ID:1603588

Huff, Tyler C. ^[1];

^[1]; Sant, David W. ^[1]; Wilkes, Zachary ^[1]; Van Booven, Derek ^[1]; Aron, Allegra T. ^[2]; Muir, Ryan K. ^[3];

^[3]; Chang, Christopher J. ^[2]; Monje, Paula V. ^[4];

^[1]

Univ. of Miami Miller School of Medicine, Miami, FL, USA
Univ. of California, Berkeley, CA (United States)
Univ. of California, San Francisco, CA (United States)
Indiana Univ. School of Medicine, Indianapolis, IN (United States)

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).

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231; R01NS089525; GM079465; 339576; T32 GM066698

OSTI ID:: 1603588

Journal Information:: Life Science Alliance, Vol. 3, Issue 1; ISSN 2575-1077

Publisher:: Cold Spring Harbor Laboratory PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 4 works

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Title: Oscillatory cAMP signaling rapidly alters H3K4 methylation

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