Jmjd2C increases MyoD transcriptional activity through inhibiting G9a-dependent MyoD degradation

Jung, Eun-Shil; Sim, Ye-Ji; Jeong, Hoe-Su; Kim, Sujin; Yun, Ye-Jin; Song, Joo-Hoon; Jeon, Su-Hee; Choe, Chungyoul; Park, Kyung‐Tae; Kim, Chang Hoon; Kim, Kye-Seong

doi:10.1016/j.bbagrm.2015.07.001

Cited by 37 publications

(34 citation statements)

References 36 publications

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“…Recently, we reported that G9a activates MYOD protein degradation in a methylation-dependent manner (Jung et al., 2015). We examined whether G9a activates DNMT3A/B protein degradation.…”

Section: Resultsmentioning

confidence: 99%

“…G9a contains a SET domain with ankyrin repeats and mediates the transfer of one to three methyl groups from S-adenosylmethionine to the amino group of a target lysine (Esteve et al., 2005), resulting in gene silencing (Dillon et al., 2005, Tachibana et al., 2001). G9a also methylates non-histone proteins, such as p53, WIZ, CDYL1, ACINUS, REPTIN, MYOD, and DNMT1, to regulate chromatin structure and transcriptional machinery (Jung et al., 2015, Ling et al., 2012, Rathert et al., 2008). The mechanism underlying G9a-mediated DNMT3A/B regulation in ESCs is not well understood.…”

Section: Introductionmentioning

confidence: 99%

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2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms

et al. 2017

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SummaryMouse embryonic stem cells (ESCs) are maintained in serum with leukemia inhibitory factor (LIF) to maintain self-renewal and pluripotency. Recently, a 2i culture method was reported using a combination of MEK inhibition (MEKi) and GSK3 inhibition (GSK3i) with LIF to maintain ESCs in a naive ground state. How 2i maintains a ground state of ESCs remains elusive. Here we show that MEKi and GSK3i maintain the ESC ground state by downregulating global DNA methylation through two distinct mechanisms. MEK1 phosphorylates JMJD2C for ubiquitin-mediated protein degradation. Therefore, MEKi increased JMJD2C protein levels but decreased DNMT3 expression. JMJD2C promotes TET1 activity to increase 5-hydroxymethylcytosine (5hmC) levels. GSK3i suppressed DNMT3 expression, thereby decreasing DNA methylation without affecting 5hmC levels. Furthermore, 2i increased PRDM14 expression to inhibit DNMT3A/B protein expression by promoting G9a-mediated DNMT3A/B protein degradation. Collectively, 2i allows ESCs to maintain a naive ground state through JMJD2C-dependent TET1 activation and PRDM14/G9a-mediated DNMT3A/B protein degradation.

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“…Recently, we reported that G9a activates MYOD protein degradation in a methylation-dependent manner (Jung et al., 2015). We examined whether G9a activates DNMT3A/B protein degradation.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms

et al. 2017

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“…However, in other contexts lysine methylation promotes protein degradation; 87 for example, methylation by Ehmt2 has been show to target MyoD for ubiquitination and proteasomal degradation. 88 Therefore, it is likely that Ehmt2's role in protein stability is also highly context dependant and that in some cases, Ehmt2s role in negatively regulating protein function may be in part due to its promoting target protein degradation.…”

Section: Emerging Roles Of Ehmt2mentioning

confidence: 99%

The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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Epigenetic regulators play a crucial role in neurodevelopment. One such epigenetic complex, Ehmt1/2 (G9a/GLP), is essential for repressing gene transcription by methylating H3K9 in a highly tissue-and temporal-specific manner. Recently, data has emerged suggesting that this complex plays additional roles in regulating the activity of numerous other non-histone proteins. While much is known about the downstream effects of Ehmt1/2 function, evidence is only beginning to come to light suggesting the control of Ehmt1/2 function may be, at least in part, due to context-dependent binding partners. Here we review emerging roles for the Ehmt1/2 complex suggesting that it may play a much larger role than previously recognized, and discuss binding partners that we and others have recently characterized which act to coordinate its activity during early neurodevelopment.

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“…One report indicates that a novel isoform of the KDM4A demethylase that is upregulated upon differentiation signaling mediates H3K9 demethylation and is required for myogenic differentiation (68). KDM4A also demethylates MyoD, which results in increased protein stability (69). Additional investigation is warranted.…”

Section: The Chromatin State At Active Myogenic Locimentioning

confidence: 99%

Temporal regulation of chromatin during myoblast differentiation

Harada

Ohkawa

2017

Seminars in Cell & Developmental Biology

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The commitment to and execution of differentiation programs involves a significant change in gene expression in the precursor cell to facilitate development of the mature cell type. In addition to being regulated by lineage-determining and auxiliary transcription factors that drive these changes, the structural status of the chromatin has a considerable impact on the transcriptional competence of differentiation-specific genes, which is clearly demonstrated by the large number of cofactors and the extraordinary complex mechanisms by which these genes become activated. The terminal differentiation of myoblasts to myotubes and mature skeletal muscle is an excellent system to illustrate these points. The MyoD family of closely related, lineage-determining transcription factors directs, largely through targeting to chromatin, a cascade of cooperating transcription factors and enzymes that incorporate or remove variant histones, post-translationally modify histones, and alter nucleosome structure and positioning via energy released by ATP hydrolysis. The coordinated action of these transcription factors and enzymes prevents expression of differentiation-specific genes in myoblasts and facilitates the transition of these genes from transcriptionally repressed to activated during the differentiation process. Regulation is achieved in both a temporal as well as spatial manner, as at least some of these factors and enzymes affect local chromatin structure at myogenic gene regulatory sequences as well as higher-order genome organization. Here we discuss the transition of genes that promote myoblast differentiation from the silenced to the activated state with an emphasis on the changes that occur to individual histones and the chromatin structure present at these loci.

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Jmjd2C increases MyoD transcriptional activity through inhibiting G9a-dependent MyoD degradation

Cited by 37 publications

References 36 publications

2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms

2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms

The expanding role of the Ehmt2/G9a complex in neurodevelopment

Temporal regulation of chromatin during myoblast differentiation

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