title: Nuclear cGMP-dependent kinase regulates gene expression via activity-dependent recruitment of a conserved histone deacetylase complex.
abstract: 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.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hao
authors.forename: Ningyi
authors.initials: N
authors.lastname: Xu
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Box
authors.forename: Laura
authors.initials: L
authors.lastname: Schaefer
authors.forename: Kasthuri
authors.initials: K
authors.lastname: Kannan
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.forename: Christopher
authors.initials: C
authors.lastname: Seidel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.forename: Winfried
authors.initials: W
authors.lastname: Wiegraebe
authors.forename: Ho Yi
authors.initials: HY
authors.lastname: Mak
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D012098:Reproduction / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D017869:Cyclic GMP-Dependent Protein Kinases; C470349:EGL-4 protein, C elegans; D006655:Histone Deacetylases