Nuclear CGMP-dependent Kinase Regulates Gene Expression Via Activity-dependent Recruitment of a Conserved Histone Deacetylase Complex
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Elevation of the second messenger cGMP by nitric oxide (NO) activates the cGMP-dependent protein kinase PKG, which is key in regulating cardiovascular, intestinal, and neuronal functions in mammals. The NO-cGMP-PKG signaling pathway is also a major therapeutic target for cardiovascular and male reproductive diseases. Despite widespread effects of PKG activation, few molecular targets of PKG are known. We study how EGL-4, the Caenorhabditis elegans PKG ortholog, modulates foraging behavior and egg-laying and seeks the downstream effectors of EGL-4 activity. Using a combination of unbiased forward genetic screen and proteomic analysis, we have identified a conserved SAEG-1/SAEG-2/HDA-2 histone deacetylase complex that is specifically recruited by activated nuclear EGL-4. Gene expression profiling by microarrays revealed >40 genes that are sensitive to EGL-4 activity in a SAEG-1-dependent manner. We present evidence that EGL-4 controls egg laying via one of these genes, Y45F10C.2, which encodes a novel protein that is expressed exclusively in the uterine epithelium. Our results indicate that, in addition to cytoplasmic functions, active EGL-4/PKG acts in the nucleus via a conserved Class I histone deacetylase complex to regulate gene expression pertinent to behavioral and physiological responses to cGMP. We also identify transcriptional targets of EGL-4 that carry out discrete components of the physiological response.
Vogt M, Hobert O Sci Adv. 2023; 9(14):eade1817.
PMID: 37027477 PMC: 10081852. DOI: 10.1126/sciadv.ade1817.
The MLL3/4 complexes and MiDAC co-regulate H4K20ac to control a specific gene expression program.
Wang X, Rosikiewicz W, Sedkov Y, Mondal B, Martinez T, Kallappagoudar S Life Sci Alliance. 2022; 5(11).
PMID: 35820704 PMC: 9275676. DOI: 10.26508/lsa.202201572.
Unno T, Takatsuka H, Ohnishi Y, Ito M, Kubota Y Genes Genomics. 2021; 44(3):343-357.
PMID: 34843089 DOI: 10.1007/s13258-021-01195-9.
Yan J, Chen Y, Zhu Y, Paquet-Durand F Int J Mol Sci. 2021; 22(19).
PMID: 34638907 PMC: 8508647. DOI: 10.3390/ijms221910567.
piRNAs and endo-siRNAs: Small molecules with large roles in the nervous system.
Ow M, Hall S Neurochem Int. 2021; 148:105086.
PMID: 34082061 PMC: 8286337. DOI: 10.1016/j.neuint.2021.105086.