Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases

Vaute, Olivier; Nicolas, Estelle; Vandel, Laurence; Trouche, Didier

doi:10.1093/nar/30.2.475

Cited by 149 publications

(129 citation statements)

References 45 publications

(89 reference statements)

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“…SUV39H1 methylates histone H3 at lysine 9 and serves as a specific-binding site for the recruitment of HP1 (Zhang and Reinberg, 2001;Stewart et al, 2005). Histone 3 lysine 9 methylation (H3-K9) plays an essential role in heterochromatin formation which correlates with repression of gene expression (Vaute et al, 2002;Sims et al, 2003;Stewart et al, 2005;Wu et al, 2005). In the present study, we have discovered a splice variant of the HP1 gene in 8-16 stage embryos regardless of the production method.…”

Section: Discussionmentioning

confidence: 47%

Messenger RNA expression patterns of histone‐associated genes in bovine preimplantation embryos derived from different origins

Nowak‐Imialek¹,

Wrenzycki

Herrmann³

et al. 2007

Molecular Reproduction Devel

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Histone modification genes in bovine embryos: The mRNA expression pattern of histone-related genes was determined in bovine oocytes and embryos. We compared immature and in vitro-matured oocytes, either before or after enucleation and activation, in vitro produced embryos (zygotes, 8-16 cell stages, blastocysts), embryos cloned with female or male donor cells; parthenogenetic embryos, and in vivo-derived blastocysts to detect deviations from the normal expression pattern. A sensitive semi-quantitative endpoint RT-PCR assay was used to reveal differences in histone deacetylation [histone deacetylase 2 (HDAC2)]; histone acetylation [histone acetyltransferase 1 (HAT1)]; histone methylation [histone methyltransferases (SUV39H1, G9A)]; heterochromatin formation [heterochromatin protein 1 (HP1)]; and chromatin-mediated transcription regulation [zygote arrest 1 (ZAR1)]. With the exception of ZAR1, these mRNAs were present throughout preimplantation development. The relative abundance of mRNAs for histone methyltransferases (SUV39H1 and G9A) and for heterochromatin-associated protein (HP1) differed significantly before and after activation of the bovine embryonic genome. The similarity of HAT1 gene expression in 8-16 cell embryos and blastocysts suggests that histone acetylation is primarily affected by in vitro culture only prior to embryonic genome activation. HDAC2 gene mRNA expression was not affected by in vitro culture and/or cloning before and after activation of the embryonic genome. The donor cell line affected mRNA expression patterns of genes involved in reprogramming cloned embryos suggesting epigenetic dysregulation. Results show that both in vitro production and somatic cloning alter the mRNA expression of histone modifying genes in bovine embryos. Mol.

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Section: Discussionmentioning

confidence: 47%

Messenger RNA expression patterns of histone‐associated genes in bovine preimplantation embryos derived from different origins

Nowak‐Imialek¹,

Wrenzycki

Herrmann³

et al. 2007

Molecular Reproduction Devel

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“…ESET is also involved in maintaining heterochromatin. As a HMT, ESET may form complexes with other chromatin remodeling enzymes in modulating gene transcription (34). We show that ESET expression is markedly increased in HD patients and in R6/2 transgenic HD mice and that ESET specifically methylates and increases the protein level of trimethylated histone H3 (K9), a marker of gene silencing.…”

Section: Discussionmentioning

confidence: 92%

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease

Ryu

Lee

Hagerty

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

288

252

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Chromatin remodeling and transcription regulation are tightly controlled under physiological conditions. It has been suggested that altered chromatin modulation and transcription dysfunction may play a role in the pathogenesis of Huntington's disease (HD). Increased histone methylation, a well established mechanism of gene silencing, results in transcriptional repression. ERG-associated protein with SET domain (ESET), a histone H3 (K9) methyltransferase, mediates histone methylation. We show that ESET expression is markedly increased in HD patients and in transgenic R6/2 HD mice. Similarly, the protein level of trimethylated histone H3 (K9) was also elevated in HD patients and in R6/2 mice. We further demonstrate that both specificity protein 1 (Sp1) and specificity protein 3 (Sp3) act as transcriptional activators of the ESET promoter in neurons and that mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic, interferes with the DNA binding of these Sp family transcription factors, suppressing basal ESET promoter activity in a dose dependent manner. The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9). This polytherapy significantly ameliorated the behavioral and neuropathological phenotype in the R6/2 mice and extended survival over 40%, well beyond any existing reported treatment in HD mice. Our data suggest that modulation of gene silencing mechanisms, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in HD patients. H untington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded stretches of CAG repeats coding for glutamine in the Huntingtin (Htt) gene. Polyglutamine [poly(Q)] expansions of mutant Htt (mtHtt) protein lead to a number of cellular abnormalities that include altered nucleosome dynamics and subsequent transcriptional dysregulation (1-4). Consistent with transcriptional repression playing a role in the pathogenesis of HD, decreased acetylation and increased methylation of histones, well established mechanisms of gene activation and silencing, have been found in HD experimental models (5-8). Histone acetylation is involved in the regulation of gene expression and is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs) (9). The poly(Q) stretches in mtHtt interact physically with CREB binding protein (CBP), a transcriptional coactivator, and block intrinsic CBP histone acetyltransferase activity (2, 5). These specific interactions have led to a model in which mtHtt, by harboring extra glutamines, becomes a hyperactive glutamine-containing corepressor (10). Transcriptional repression may also be attributable to epigenetic modifications, such as histone methylation and histone deacetylation (11). Thus, transcriptional dysfunction has been proposed to play an important role in the neuronal cell death of HD and has be...

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“…9 Both SUV39H1 and G9a act in multiple repressive complexes and interact with regulatory elements to silence transcription. 12,13,29 The inhibition of these two histone methyltransferases can induce a shift from repressive to activating posttranslational histone modifications beyond H3 demethylation. Our observation that the knockdown of the transcriptional repressor G9a alone increases global H3K9 acetylation levels ( Figure 2A) -a sign for transcriptional derepression -is consistent with findings of others.…”

Section: Discussionmentioning

confidence: 99%

“…11 Both SUV39H1 and G9a are found in diverse repressive complexes and act in concert with other epigenetic players, such as DNA methyltransferases 12 and diverse HDACs. 13 As such they contribute to the induction and maintenance of transcriptional repression in the genome.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Histone Methyltransferases SUV39H1 and G9a Leads to Neuroprotection in an in vitro Model of Cerebral Ischemia

Schweizer

Harms

Lerch

et al. 2015

J Cereb Blood Flow Metab

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Cerebral ischemia induces a complex transcriptional response with global changes in gene expression. It is essentially regulated by transcription factors as well as epigenetic players. While it is well known that the inhibition of transcriptionally repressive histone deacetylases leads to neuroprotection, the role of histone methyltransferases in the postischemic transcriptional response remains elusive. We investigated the effects of inhibition of the repressive H3K9 histone methyltransferases SUV39H1 and G9a on neuronal survival, H3K9 promoter signatures and gene expression. Their inhibition either with the specific blocker chaetocin or by use of RNA interference promoted neuronal survival in oxygen glucose deprivation (OGD). Brain-derived neurotrophic factor (BDNF) was upregulated and BDNF promoter regions showed an increase in histone marks characteristic for active transcription. The BDNF blockade with K252a abrogated the protective effect of chaetocin treatment. In conclusion, inhibition of histone methyltransferases SUV39H1 and G9a confers neuroprotection in a model of hypoxic metabolic stress, which is at least in part mediated by BDNF.

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Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases

Cited by 149 publications

References 45 publications

Messenger RNA expression patterns of histone‐associated genes in bovine preimplantation embryos derived from different origins

Messenger RNA expression patterns of histone‐associated genes in bovine preimplantation embryos derived from different origins

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease

Inhibition of Histone Methyltransferases SUV39H1 and G9a Leads to Neuroprotection in an in vitro Model of Cerebral Ischemia

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