Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa

Tamaru, Hisashi; Zhang, Xing; McMillen, Debra A.; Singh, Prim B.; Nakayama, Jun‐ichi; Grewal, Shiv I. S.; Allis, C. David; Cheng, Xiaodong; Selker, Eric U.

doi:10.1038/ng1143

Cited by 349 publications

(305 citation statements)

References 30 publications

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“…Furthermore, HKMT enzymes also modify the appropriate lysine to a specific degree (i.e., mono-, di-and/or tri-methyl state). Maintaining the same examples, DIM5 can tri-methylate H3K9 [21] but SET7/9 can only mono-methylate H3K4 [22]. These specific reaction products can be generated using only the purified enzymes; so the ability to discriminate between different histone lysines and between different methylated states is an intrinsic property of the enzyme.…”

Section: Lysine Methylationmentioning

confidence: 99%

Regulation of chromatin by histone modifications

2011

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Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.

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Section: Lysine Methylationmentioning

confidence: 99%

Regulation of chromatin by histone modifications

2011

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“…ESET contains both tudor and methylCpG binding domains that converge transcription and RNA processing factors, as well as acting as a signature motif for proteins regulating methylated DNA silencing. ESET interacts with a number of enzymes and transcription factors that include HDAC1 and -2, mSin3A and -3B, HP1, and MBD1 (19)(20)(21). As such, ESET may be involved in the epigenetic silencing of neuronal genes through its HMT activity (22).…”

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confidence: 99%

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.

291

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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“…DIM-5 of N. crassa, on the other hand, generates primarily trimethyl Lys-9, which marks chromatin regions for DNA methylation [49]. Considering that different methylation products might have different signaling properties [49][50][51], it is important to understand the structural basis for this product specificity [27].…”

Section: A Tyrosine/phenylalanine Switch Controls Product Specificitymentioning

confidence: 99%

“…DIM-5 and SET7/9 generate distinct products: DIM-5 forms trimethyl-lysine ( Figure 3a) [27,49] and SET7/9 forms only monomethyl-lysine ( Figure 3d) [27,32]. A likely structural explanation for their different product specificities is that residues in the lysine-binding channel of SET7/9 sterically exclude the target lysine side chain with methyl group(s).…”

Section: A Tyrosine/phenylalanine Switch Controls Product Specificitymentioning

confidence: 99%

Structural dynamics of protein lysine methylation and demethylation

Cheng

Zhang

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Lysine methylation plays a central role in the "histone code" that regulates chromatin structure, impacts transcription, and responds to DNA damage. A single lysine can be mono-, di-, trimethylated, or unmethylated, with different functional consequences for each of the four forms. This review describes structural aspects of methylation of histone lysine residues by two enzyme families with entirely different structural scaffolding (the SET proteins and Dot1p), and the protein motifs that recognize (decode) these methyl-lysine signals. We also discuss the recently discovered protein lysine de-methylating enzymes (LSD1 and JmjC domains). Keywordsprotein lysine methylation and demethylation; SET domain proteins; S-adenosyl-L-methionine (AdoMet)

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Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa

Cited by 349 publications

References 30 publications

Regulation of chromatin by histone modifications

Regulation of chromatin by histone modifications

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

Structural dynamics of protein lysine methylation and demethylation

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