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 language | English |
|---|---|
| Article number | e201900529 |
| Journal | Life Science Alliance |
| Volume | 3 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2020 |
Bibliographical note
Publisher Copyright:© 2019 Huff et al.
Funding
This work is supported by National Institutes of Health (NIH) grants (R01NS089525 to G Wang and GM079465 to CJ Chang) and a Craig H Neilsen Foundation grant (#339576 to PV Monje). G Wang is supported by Sylvester NIH Funding Program from Sylvester Comprehensive Cancer Center at the University of Miami. CJ Chang is an Investigator with the Howard Hughes Medical Institute and a Canadian Institute for Advanced Research Senior Fellow. AT Aron thanks the NSF for a graduate fellowship and was partially supported by a Chemical Biology Training Grant from the NIH (T32 GM066698). The authors would like to thank the National Institute of Mental Health for providing NS1 WT and NS1 RapGEF2 KO cells.
| Funders | Funder number |
|---|---|
| NIH Funding | |
| Sylvester Comprehensive Cancer Center | |
| Sylvester NIH | |
| National Science Foundation Arctic Social Science Program | T32 GM066698 |
| National Science Foundation Arctic Social Science Program | |
| National Institutes of Health (NIH) | R01NS089525, GM079465 |
| National Institutes of Health (NIH) | |
| Howard Hughes Medical Institute | |
| National Institute of Mental Health | |
| National Institute of General Medical Sciences | T32GM064337 |
| National Institute of General Medical Sciences | |
| National Sleep Foundation | |
| Craig H. Neilsen Foundation | 339576 |
| Craig H. Neilsen Foundation | |
| Miami Clinical and Translational Science Institute, University of Miami | |
| Canadian Institute for Advanced Research |
ASJC Scopus subject areas
- Ecology
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Plant Science
- Health, Toxicology and Mutagenesis