A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation

Singh, Kulwant; Cassano, Marco; Planet, Evarist; Sebastian, Soji; Jang, Suk Min; Sohi, Gurjeev; Faralli, Hervé; Choi, Jinmi; Youn, Hwa Young; Dilworth, F. Jeffrey; Trono, Didier

doi:10.1101/gad.254532.114

Cited by 67 publications

(82 citation statements)

References 63 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It generally serves as a scaffold for the assembly of macromolecular complexes containing diverse chromatin modifiers, including histone methyltransferases, histone acetylases and deacetylases, as well as nucleosome remodeling factors. Initially identified as a corepressor, notably found responsible for the early embryonic silencing of KZFP‐targeted endogenous endogenous retroelements, TRIM28 has since been demonstrated to be capable of acting also as a coactivator and has been implicated not only in transcriptional regulation, but also in DNA repair and maintenance of heterochromatin during genome replication …”

Section: Discussionmentioning

confidence: 99%

Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice

et al. 2017

Self Cite

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) represents the fifth‐most common form of cancer worldwide and carries a high mortality rate attributed to lack of effective treatment. Males are 8 times more likely to develop HCC than females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28 (tripartite protein 28), a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver. Trim28hep–/– mice display sex‐specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and aging precipitate alterations of TRIM28‐dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male‐restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances, and altered responses to gut microbiota in the pathogenesis of Trim28hep–/–‐associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high‐fat diet challenge. Conclusion: This work underpins how discrete polyphenic traits in epigenetically metastable conditions can contribute to a cancer‐prone state and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota, and cancer. (Hepatology 2017;66:235–251).

show abstract

Section: Discussionmentioning

confidence: 99%

Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our results indicate that the nuclear interaction of WTX and TRIM28 modulates a later stage in mesenchymal cell differentiation. While this manuscript was under revision, Singh et al (36) reported that TRIM28 modulates the function of MyoD, a master regulator of mesenchyme to skeletal muscle differentiation. Further tissue-specific analyses using conditional inactivation models will be required to fully dissect the potential functional interactions between WTX and TRIM28 in vivo.…”

Section: Discussionmentioning

confidence: 99%

The WTX Tumor Suppressor Interacts with the Transcriptional Corepressor TRIM28

Kim

Wittner

Amzallag

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The Wilms tumor suppressor WTX localizes to both nucleus and cytoplasm, but its nuclear function is not understood. Results: Nuclear WTX co-immunoprecipitates with the transcriptional corepressor TRIM28, modulating its chromatin binding and coregulating the expression of DNA repeat elements. Conclusion: WTX contributes to silencing of heterochromatic repeats. Significance: WTX may modulate tumorigenesis and cell differentiation in part through its effect on chromatin regulation.

show abstract

“…At the onset of myoblast differentiation, predominant signaling pathways such as p38α MAPK and PI3/AKT play a major role in transitioning from a transcriptionally repressive to permissive chromatin environment for MyoD-initiated myogenic differentiation program [28–32]. By contrast, p38γ MAPK represses myogenic differentiation by facilitating the association of MyoD with KMT1A in growing myoblasts [33].…”

Section: Introductionmentioning

confidence: 99%

p38α MAPK disables KMT1A-mediated repression of myogenic differentiation program

et al. 2016

View full text Add to dashboard Cite

BackgroundMaster transcription factor MyoD can initiate the entire myogenic gene expression program which differentiates proliferating myoblasts into multinucleated myotubes. We previously demonstrated that histone methyltransferase KMT1A associates with and inhibits MyoD in proliferating myoblasts, and must be removed to allow differentiation to proceed. It is known that pro-myogenic signaling pathways such as PI3K/AKT and p38α MAPK play critical roles in enforcing associations between MyoD and transcriptional activators, while removing repressors. However, the mechanism which displaces KMT1A from MyoD, and the signals responsible, remain unknown.MethodsTo investigate the role of p38α on MyoD-mediated differentiation, we utilized C2C12 myoblast cells as an in vitro model. p38α activity was either augmented via overexpression of a constitutively active upstream kinase or blocked via lentiviral delivery of a specific p38α shRNA or treatment with p38α/β inhibitor SB203580. Overexpression of KMT1A in these cells via lentiviral delivery was also used as a system wherein terminal differentiation is impeded by high levels of KMT1A.ResultsThe association of KMT1A and MyoD persisted, and differentiation was blocked in C2C12 myoblasts specifically after pharmacologic or genetic blockade of p38α. Conversely, forced activation of p38α was sufficient to activate MyoD and overcome the differentiation blockade in KMT1A-overexpressing C2C12 cells. Consistent with this finding, KMT1A phosphorylation during C2C12 differentiation correlated strongly with the activation of p38α. This phosphorylation was prevented by the inhibition of p38α. Biochemical studies further revealed that KMT1A can be a direct substrate for p38α. Importantly, chromatin immunoprecipitation (ChIP) studies show that the removal of KMT1A-mediated transcription repressive histone tri-methylation (H3K9me3) from the promoter of the Myogenin gene, a critical regulator of muscle differentiation, is dependent on p38α activity in C2C12 cells. Elevated p38α activity was also sufficient to remove this repressive H3K9me3 mark. Moreover, ChIP studies from C2C12 cells show that p38α activity is necessary and sufficient to establish active H3K9 acetylation on the Myogenin promoter.ConclusionsActivation of p38α displaces KMT1A from MyoD to initiate myogenic gene expression upon induction of myoblasts differentiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0100-z) contains supplementary material, which is available to authorized users.

show abstract

A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation

Cited by 67 publications

References 63 publications

Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice

Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice

The WTX Tumor Suppressor Interacts with the Transcriptional Corepressor TRIM28

p38α MAPK disables KMT1A-mediated repression of myogenic differentiation program

Contact Info

Product

Resources

About