Nuclear cGMP-dependent kinase regulates gene expression via activity-dependent recruitment of a conserved histone deacetylase complex

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. © 2011 hao et al.