Nuclear cGMP-Dependent Kinase Regulates Gene Expression via Activity-Dependent Recruitment of a Conserved Histone Deacetylase Complex

Hao, Yan; Xu, Ningyi; Box, Andrew; Schaefer, Laura; Kannan, Kasthuri; Zhang, Ying; Florens, Laurence; Seidel, Christopher; Washburn, Michael P.; Wiegraebe, Winfried; Mak, Ho Yi

doi:10.1371/journal.pgen.1002065

Cited by 42 publications

(38 citation statements)

References 60 publications

(64 reference statements)

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“…It is feasible that the PDE1 inhibitor IC86340 primarily elevates nuclear and perinuclear cGMP levels, and the elevation of peripheral cGMP levels occurs through rapid intracellular diffusion [31]. While the functional relevance of nuclear/perinuclear cGMP is not well described, a recent study suggests nuclear cGMP/PKG modulates gene expression via recruitment of a histone deacetylase complex [24]. These data together add to our understanding of tightly regulated and compartmentalized cGMP signaling by multiple PDEs within a given cell.…”

Section: Discussionmentioning

confidence: 99%

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

et al. 2011

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Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca2+/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.

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Section: Discussionmentioning

confidence: 99%

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

et al. 2011

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“…EGL-4 seems to be a multifunctional regulator with apparently unrelated functions, because egl-4 mutations cause not only the body size phenotype but also a wide variety of phenotypes including defects in the control of egg laying, dauer formation, fat storage, chemosensory behavior, locomotory state, life span, sleep-like state, and even satiety signaling (Trent et al 1983;Daniels et al 2000;L'Etoile et al 2002;Hirose et al 2003;Raizen et al 2006;Raizen et al 2008;You et al 2008;Hao et al 2011;O'halloran et al 2012). Therefore, EGL-4 activity upstream of each of these functions is likely to be controlled separately in C. elegans.…”

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confidence: 99%

The Importance of cGMP Signaling in Sensory Cilia for Body Size Regulation in Caenorhabditis elegans

et al. 2015

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The body size of Caenorhabditis elegans is thought to be controlled by sensory inputs because many mutants with sensory cilium structure defects exhibit small body size. The EGL-4 cGMP-dependent protein kinase acts in sensory neurons to reduce body size when animals fail to perceive sensory signals. In addition to body size control, EGL-4 regulates various other behavioral and developmental pathways, including those involved in the regulation of egg laying and chemotaxis behavior. Here we have identified gcy-12, which encodes a receptor-type guanylyl cyclase, as a gene involved in the sensory regulation of body size. Analyses with GFP fusion constructs showed that gcy-12 is expressed in several sensory neurons and localizes to sensory cilia. Genetic analyses indicated that GCY-12 acts upstream of EGL-4 in body size control but does not affect other EGL-4 functions. Our studies indicate that the function of the GCY-12 guanylyl cyclase is to provide cGMP to the EGL-4 cGMP-dependent kinase only for limited tasks including body size regulation. We also found that the PDE-2 cyclic nucleotide phosphodiesterase negatively regulates EGL-4 in controlling body size. Thus, the cGMP level is precisely controlled by GCY-12 and PDE-2 to determine body size through EGL-4, and the defects in the sensory cilium structure may disturb the balanced control of the cGMP level. The large number of guanylyl cyclases encoded in the C. elegans genome suggests that EGL-4 exerts pleiotropic effects by partnering with different guanylyl cyclases for different downstream functions.

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“…Among proteins showing the most extreme CNV values, we observed Vitellogenin‐1 (CNV value of +1.5), a precursor of egg‐yolk proteins, the Y45F10C.4 protein (CNV value of +2.1), and the UPF0375 protein Y45F10C.2. The latter protein, known to negatively regulate the egg‐laying rate (Hao et al , 2011), shows a SILAC ratio of −7.4 on day 1 and increases it to +2.7 on day 22. However, its CNV value is low (−1.6), indicating that the abundance of this protein is not increasing at the same rate as other extracellular proteins.…”

Section: Resultsmentioning

confidence: 99%

Quantifying compartment‐associated variations of protein abundance in proteomics data

Parca

Beck

Bork

et al. 2018

Molecular Systems Biology

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Quantitative mass spectrometry enables to monitor the abundance of thousands of proteins across biological conditions. Currently, most data analysis approaches rely on the assumption that the majority of the observed proteins remain unchanged across compared samples. Thus, gross morphological differences between cell states, deriving from, e.g., differences in size or number of organelles, are often not taken into account. Here, we analyzed multiple published datasets and frequently observed that proteins associated with a particular cellular compartment collectively increase or decrease in their abundance between conditions tested. We show that such effects, arising from underlying morphological differences, can skew the outcome of differential expression analysis. We propose a method to detect and normalize morphological effects underlying proteomics data. We demonstrate the applicability of our method to different datasets and biological questions including the analysis of sub‐cellular proteomes in the context of Caenorhabditis elegans aging. Our method provides a complementary perspective to classical differential expression analysis and enables to uncouple overall abundance changes from stoichiometric variations within defined group of proteins.

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Nuclear cGMP-Dependent Kinase Regulates Gene Expression via Activity-Dependent Recruitment of a Conserved Histone Deacetylase Complex

Cited by 42 publications

References 60 publications

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

The Importance of cGMP Signaling in Sensory Cilia for Body Size Regulation in Caenorhabditis elegans

Quantifying compartment‐associated variations of protein abundance in proteomics data

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