Sir2 Regulates Skeletal Muscle Differentiation as a Potential Sensor of the Redox State

Fulco, Marcella; Schiltz, R. Louis; Iezzi, Simona; King, Michael; Zhao, Po; Kashiwaya, Yoshiaki; Hoffman, Eric P.; Veech, Richard L.; Sartorelli, Vittorio

doi:10.1016/s1097-2765(03)00226-0

Cited by 536 publications

(285 citation statements)

References 42 publications

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“…Our results suggest that SIRT1 might be the primary deacetylase rendering SOX9 in a hypo‐acetylated state, similar to its action on various other regulators as β‐catenin, MyoD, and RelA (Fulco et al ., 2003; Yeung et al ., 2004; Simic et al ., 2013). A previous study, by Baltus et al .…”

Section: Discussionmentioning

confidence: 99%

Acetylation reduces SOX 9 nuclear entry and ACAN gene transactivation in human chondrocytes

Kumar

Elayyan

et al. 2016

Aging Cell

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SummaryChanges in the content of aggrecan, an essential proteoglycan of articular cartilage, have been implicated in the pathophysiology of osteoarthritis (OA), a prevalent age‐related, degenerative joint disease. Here, we examined the effect of SOX9 acetylation on ACAN transactivation in the context of osteoarthritis. Primary chondrocytes freshly isolated from degenerated OA cartilage displayed lower levels of ACAN mRNA and higher levels of acetylated SOX9 compared with cells from intact regions of OA cartilage. Degenerated OA cartilage presented chondrocyte clusters bearing diffused immunostaining for SOX9 compared with intact cartilage regions. Primary human chondrocytes freshly isolated from OA knee joints were cultured in monolayer or in three‐dimensional alginate microbeads (3D). SOX9 was hypo‐acetylated in 3D cultures and displayed enhanced binding to a −10 kb ACAN enhancer, a result consistent with higher ACAN mRNA levels than in monolayer cultures. It also co‐immunoprecipitated with SIRT1, a major deacetylase responsible for SOX9 deacetylation. Finally, immunofluorescence assays revealed increased nuclear localization of SOX9 in primary chondrocytes treated with the NAD SIRT1 cofactor, than in cells treated with a SIRT1 inhibitor. Inhibition of importin β by importazole maintained SOX9 in the cytoplasm, even in the presence of NAD. Based on these data, we conclude that deacetylation promotes SOX9 nuclear translocation and hence its ability to activate ACAN.

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Section: Discussionmentioning

confidence: 99%

Acetylation reduces SOX 9 nuclear entry and ACAN gene transactivation in human chondrocytes

Kumar

Elayyan

et al. 2016

Aging Cell

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“…In addition to introducing and removing acetyl groups at amino acid residues of histone tails, histone acetyltransferases and histone deacetylases also modify discrete lysine residues of MyoD and Mef2 (6,7,31) (15,32,33,34,35). Acetylation of MyoD and Mef2 exerts regulatory functions on gene expression.…”

Section: Discussionmentioning

confidence: 99%

MyoD Acetylation Influences Temporal Patterns of Skeletal Muscle Gene Expression

Padova

Caretti

Zhao

et al. 2007

Journal of Biological Chemistry

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MyoD is sufficient to initiate the skeletal muscle gene expression program. Transcription of certain MyoD target genes occurs in the early phases, whereas that of others is induced only at later stages, although MyoD is present throughout the differentiation process. MyoD acetylation regulates transcriptional competency, yet whether this post-translational modification is equally relevant for activation of all the MyoD targets is unknown. Moreover, the molecular mechanisms through which acetylation ensures that MyoD achieves its optimal activity remain unexplored. To address these two outstanding issues, we have coupled genome-wide expression profiling and chromatin immunoprecipitation in a model system in which MyoD or its nonacetylatable version was inducibly activated in mouse embryonic fibroblasts derived from MyoD ؊/؊ /Myf5 ؊/؊ mice. Our results reveal that MyoD acetylation influences transcription of selected genes expressed at defined stages of the muscle program by regulating chromatin access of MyoD, histone acetylation, and RNA polymerase II recruitment.MyoD, Myf5, myogenin, Mrf4, and the Mef2 family of MADS box transcription factors are the prominent regulators of skeletal myogenesis (1-3). MyoD and Mef2 recruit enzymes that introduce post-translational histone modifications at the chromatin of specific genomic loci to enable site-specific and temporally regulated muscle gene expression (4). MyoD engages at least two acetyltransferases, p300 and PCAF (5), which promote acetylation of both histones and of MyoD itself. p300 and PCAF acetylate evolutionarily conserved MyoD lysines, which, when mutated to arginines, prevent full and proper transcriptional activity (6 -9). In vitro transcription experiments have indicated that although p300 acetylation is directed at histones H3 and H4, it is PCAF that acetylates MyoD (10). The functional relevance of MyoD acetylation in the animal has been confirmed in a recent study. Knock-in embryos homozygous for a mutant MyoD allele in which lysines 99 and 102 were replaced by arginines had delayed muscle regeneration and increased number of myoblasts with reduced differentiation potential (11). Although these studies indicate an overall important role of MyoD acetylation in both cultured cells and in the animal, a detailed investigation of whether MyoD acetylation impacts the temporal activation of the individual components of the muscle program is lacking. Moreover, the molecular mechanisms leading to defective transcription of nonacetylatable MyoD have not been clarified yet.To evaluate the contribution of MyoD acetylation at distinct, temporal-specific, stages of muscle gene activation, we have performed reiterated genome-wide expression profiling and chromatin immunoprecipitation of mouse embryonic fibroblasts (MEFs) 4 derived from MyoD Ϫ/Ϫ /Myf5 Ϫ/Ϫ animals in which MyoD activity (wild type or nonacetylatable forms) was conditionally induced. Our results indicate that acetylation is relevant to regulate a discrete set of genes at distinct stages of muscle gene e...

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“…They have been shown to regulate longevity in yeast (4 -6) and Caenorhabditis elegans (7). In mammals, it has been shown recently that the mammalian Sir2 ortholog, SIRT1/ Sir2␣, plays important roles in a variety of biological processes, such as stress and cytokine responses (8 -12), differentiation (13,14), and metabolism (14), by deacetylating transcriptional regulators. Sir2 proteins possess the unique ability to couple the breakdown of NAD and protein deacetylation to the formation of nicotinamide and O-acetyl-ADP-ribose (15,16).…”

mentioning

confidence: 99%

“…Even though the [NAD]/[NADH] ratio also modulates Sir2 function in skeletal muscle differentiation in mammals (13), it is not known whether NAD biosynthesis regulates Sir2 activity in these organisms. In fact, NAD biosynthesis in vertebrates is markedly different from that of yeast and invertebrates (Fig.…”

mentioning

confidence: 99%

The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

Revollo¹,

Grimm²,

Imai

2004

Journal of Biological Chemistry

871

792

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Recent studies have revealed new roles for NAD and its derivatives in transcriptional regulation. The evolutionarily conserved Sir2 protein family requires NAD for its deacetylase activity and regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Despite its absolute requirement for NAD, the regulation of Sir2 function by NAD biosynthesis pathways is poorly understood in mammals. In this study, we determined the kinetics of the NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (Nmnat), and we examined its effects on the transcriptional regulatory function of the mouse Sir2 ortholog, Sir2␣, in mouse fibroblasts. We found that Nampt was the ratelimiting component in this mammalian NAD biosynthesis pathway. Increased dosage of Nampt, but not Nmnat, increased the total cellular NAD level and enhanced the transcriptional regulatory activity of the catalytic domain of Sir2␣ recruited onto a reporter gene in mouse fibroblasts. Gene expression profiling with oligonucleotide microarrays also demonstrated a significant correlation between the expression profiles of Nampt-and Sir2␣-overexpressing cells. These findings suggest that NAD biosynthesis mediated by Nampt regulates the function of Sir2␣ and thereby plays an important role in controlling various biological events in mammals.

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Sir2 Regulates Skeletal Muscle Differentiation as a Potential Sensor of the Redox State

Cited by 536 publications

References 42 publications

Acetylation reduces SOX 9 nuclear entry and ACAN gene transactivation in human chondrocytes

Acetylation reduces SOX 9 nuclear entry and ACAN gene transactivation in human chondrocytes

MyoD Acetylation Influences Temporal Patterns of Skeletal Muscle Gene Expression

The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

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