CDK2-dependent phosphorylation of Suv39H1 is involved in control of heterochromatin replication during cell cycle progression

Park, Su–Hyung; Yu, Seung Eun; Chai, Young Gyu; Jang, Yong Suk

doi:10.1093/nar/gku263

Cited by 28 publications

(26 citation statements)

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“…KMT1A is a phosphoprotein and that phosphorylation modulates its function [55–57]. We found that KMT1A phosphorylation increases in myoblasts on induction of differentiation, a finding consistent to our previous study [26].…”

Section: Discussionsupporting

confidence: 91%

p38α MAPK disables KMT1A-mediated repression of myogenic differentiation program

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 91%

p38α MAPK disables KMT1A-mediated repression of myogenic differentiation program

et al. 2016

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“…24 Cdk2-mediated phosphorylation of SUV39H1 at S391 during S phase leads to its dissociation from chromatin and causes heterochromatin replication. 25 The dynamic distribution during mitosis implies that SUV39H1 may play a role during cell division that has indeed been confirmed by gene disruption studies in mice.…”

Section: Biochemical Propertiesmentioning

confidence: 77%

A drive in SUVs: From development to disease

2017

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Progression of cells through distinct phases of the cell cycle, and transition into out-of-cycling states, such as terminal differentiation and senescence, is accompanied by specific patterns of gene expression. These cell fate decisions are mediated not only by distinct transcription factors, but also chromatin modifiers that establish heritable epigenetic patterns. Lysine methyltransferases (KMTs) that mediate methylation marks on histone and non-histone proteins are now recognized as important regulators of gene expression in cycling and non-cycling cells. Among these, the SUV39 sub-family of KMTs, which includes SUV39H1, SUV39H2, G9a, GLP, SETDB1, and SETDB2, play a prominent role. In this review, we discuss their biochemical properties, sub-cellular localization and function in cell cycle, differentiation programs, and cellular senescence. We also discuss their aberrant expression in cancers, which exhibit de-regulation of cell cycle and differentiation.

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“…The PCR product was then inserted into pCMV-3Tag-6 Flag epitope-tagging mammalian expression vectors (Stratagene, La Jolla, CA). The lysine (K) to arginine (R) mutants KDM4A K463R, KDM4A K471R, KDM4A K549R, KDM4A K999R, KDM4A K1036R, and KDM4A K3R (combination of K463R/ K471R/K549R) plasmids were generated by PCR-based mutagenesis as previously described (Park et al 2014). Human SUMO1 and SUMO1 lacking a C-terminal GlyGly (SUMO1-ΔGG) were amplified by PCR and subcloned into pCMV-3Tag-2A myc-tagging mammalian expression vectors (Stratagene).…”

Section: Plasmids and Antibodiesmentioning

confidence: 99%

“…Cell lysate protein (500 µg) was incubated with FLAG M2 agarose (Sigma) overnight at 4°C as previously described (Park et al 2014), the beads were then washed five times with lysis buffer, and the immunoprecipitates were eluted by boiling the beads in 2× SDS sample buffer for 10 min. The immunoprecipitates were resolved by SDS-PAGE and transferred onto PVDF membrane for immunoblotting.…”

Section: Immunoprecipitation and In Vivo Sumoylation Assaymentioning

confidence: 99%

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Sumoylation of the histone demethylase KDM4A is required for binding to tumor suppressor p53 in HCT116 colon cancer cell lines

Park

Jang

2018

Animal Cells and Systems

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The histone demethylase lysine-specific demethylase 4A (KDM4A/Jmjd2A) has diverse functions, including involvement in gene regulation and cell cycle, and plays an oncogenic role in cancer cells. The modulation of KDM4A through post-translational modifications remains unclear. Here, we show that small ubiquitin-like modifier (SUMO) 1-mediated modification of KDM4A was required for interaction with tumor suppressor p53. Our data revealed that KDM4A is mainly sumoylated at lysine residue 471. However, the SUMO modification resulted in little change in subcellular localization, demethylase activity, or protein stability of KMD4A. Intriguingly, coimmunoprecipitation data revealed that sumoylation-defective mutants of KDM4A had a lower binding ability with p53 compared to that of wild-type KDM4A, suggesting a positive role for sumoylation in the interaction between KDM4A and p53. Together, these data suggest that KDM4A is post-translationally modified by SUMO, and this sumoylation may be a novel regulatory switch for controlling the interplay between KDM4A and p53.ARTICLE HISTORY

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CDK2-dependent phosphorylation of Suv39H1 is involved in control of heterochromatin replication during cell cycle progression

Cited by 28 publications

References 54 publications

p38α MAPK disables KMT1A-mediated repression of myogenic differentiation program

p38α MAPK disables KMT1A-mediated repression of myogenic differentiation program

A drive in SUVs: From development to disease

Sumoylation of the histone demethylase KDM4A is required for binding to tumor suppressor p53 in HCT116 colon cancer cell lines

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