Oscillatory cAMP signaling rapidly alters H3K4 methylation
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).
- Authors:
-
[1];
[3];
[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)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH)
- OSTI Identifier:
- 1603588
- Grant/Contract Number:
- AC02-05CH11231; R01NS089525; GM079465; 339576; T32 GM066698
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Life Science Alliance
- Additional Journal Information:
- Journal Volume: 3; Journal Issue: 1; Journal ID: ISSN 2575-1077
- Publisher:
- Cold Spring Harbor Laboratory Press
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; cell biology; chromatin & epigenetics
Citation Formats
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., and Wang, Gaofeng. Oscillatory cAMP signaling rapidly alters H3K4 methylation. United States: N. p., 2019.
Web. doi: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. United States. 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., and Wang, Gaofeng. Fri .
"Oscillatory cAMP signaling rapidly alters H3K4 methylation". United States. https://doi.org/10.26508/lsa.201900529. https://www.osti.gov/servlets/purl/1603588.
@article{osti_1603588,
title = {Oscillatory cAMP signaling rapidly alters H3K4 methylation},
author = {Huff, Tyler C. and Camarena, Vladimir and Sant, David W. and Wilkes, Zachary and Van Booven, Derek and Aron, Allegra T. and Muir, Ryan K. and Renslo, Adam R. and Chang, Christopher J. and Monje, Paula V. and Wang, Gaofeng},
abstractNote = {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).},
doi = {10.26508/lsa.201900529},
journal = {Life Science Alliance},
number = 1,
volume = 3,
place = {United States},
year = {2019},
month = {12}
}
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