Faculty Opinions recommendation of Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT.

Lysine to methionine (K-to-M) mutations in genes encoding histone H3 are thought to drive a subset of pediatric brain and bone cancers. These high-frequency K-to-M mutations occur at sites of methylation on histone H3, and tumors containing the mutant histones exhibit a global loss of specific histone methylation marks. Previous studies showed that K-to-M mutant histones, also known as oncohistones, are potent orthosteric inhibitors of specific Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain methyltransferases. However, the biochemical and biophysical details of the interaction between K-to-M mutant histones and the respective SET domain methyltransferases are currently unknown. Here, we use the histone H3K9-directed methyltransferase G9a as a model to explore the mechanism of inhibition by K-to-M oncohistones. X-ray cocrystal structures revealed that the K9M residue of histone H3 occupies the active site cavity of G9a, and kinetic analysis indicates competitive inhibition of G9a by histone H3K9M. Additionally, we find that the cofactor S-adenosyl methionine (SAM) is necessary for stable interaction between G9a and H3K9M histone. Consistent with the formation of a ternary complex, we find that the inhibitory peptide is uncompetitive with regard to SAM. These data and others indicate that K-to-M oncohistones promote global loss of specific lysine methylation through sequestration and inhibition of SAM-bound SET domain methyltransferases.

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Dynamic methylation of histone H3K18 in differentiating Theileria parasites

10.21203/rs.3.rs-51908/v1 ◽

2020 ◽

Author(s):

Kevin Cheeseman ◽

Guillaume Jannot ◽

Nelly Lourenco ◽

Marie Villares ◽

Jeremy BERTHELET ◽

...

Keyword(s):

Gene Expression ◽

Control Systems ◽

Cell Fate ◽

Life Cycles ◽

Epigenetic Mark ◽

Lysine Methylation ◽

Set Domain ◽

Histone Tails ◽

Complex Life Cycles ◽

Intracellular Parasites

Abstract Lysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes. Apicomplexa intracellular parasites cause major diseases and they have developed complex life cycles with fine-tuned differentiation events. Yet, apicomplexa genomes have few transcription factors and little is known about their epigenetic control systems. Tick-borne Theileria apicomplexa species have relatively small compact genomes and a remarkable ability to transform leukocytes in their bovine hosts. Here we report enriched H3 lysine 18 monomethylation (H3K18me1) on the gene bodies of repressed genes in Theileria macroschizonts. Differentiation to merozoites (merogony) led to decreased H3K18me1 in parasite nuclei. Pharmacological manipulation of H3K18 acetylation or methylation impacted parasite differentiation and expression of stage-specific genes. Finally, we identified a parasite SET-domain methyltransferase (TaSETup1) that can methylate H3K18 and represses gene expression. Thus, H3K18me1 emerges as an important epigenetic mark which controls gene expression and stage differentiation in Theileria parasites.

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SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma

10.1101/2020.10.26.354902 ◽

2020 ◽

Author(s):

Robert Hapke ◽

Lindsay Venton ◽

Kristie Lindsay Rose ◽

Quanhu Sheng ◽

Anupama Reddy ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Elongation Factor ◽

Protein Translation ◽

Lysine Methylation ◽

Set Domain ◽

Translation Elongation Factor ◽

Cell Renal Cell Carcinoma ◽

Translation Elongation

AbstractSET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. To explore SETD2-dependent regulation of the kidney cancer proteome, we performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2-knock out (KO) kidney cells. We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2. Globally, we observe differential expression of hundreds of proteins in WT versus SETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2-mutated tumors. Overall, these data suggest that SETD2-mutated ccRCC, via loss of enzymetic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.

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Dynamic methylation of histone H3K18 in differentiating Theileria parasites

Nature Communications ◽

10.1038/s41467-021-23477-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kevin Cheeseman ◽

Guillaume Jannot ◽

Nelly Lourenço ◽

Marie Villares ◽

Jérémy Berthelet ◽

...

Keyword(s):

Gene Expression ◽

Control Systems ◽

Cell Fate ◽

Life Cycles ◽

Epigenetic Mark ◽

Lysine Methylation ◽

Set Domain ◽

Histone Tails ◽

Complex Life Cycles ◽

Intracellular Parasites

AbstractLysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes. Apicomplexa intracellular parasites cause major diseases and they have developed complex life cycles with fine-tuned differentiation events. Yet, apicomplexa genomes have few transcription factors and little is known about their epigenetic control systems. Tick-borne Theileria apicomplexa species have relatively small, compact genomes and a remarkable ability to transform leucocytes in their bovine hosts. Here we report enriched H3 lysine 18 monomethylation (H3K18me1) on the gene bodies of repressed genes in Theileria macroschizonts. Differentiation to merozoites (merogony) leads to decreased H3K18me1 in parasite nuclei. Pharmacological manipulation of H3K18 acetylation or methylation impacted parasite differentiation and expression of stage-specific genes. Finally, we identify a parasite SET-domain methyltransferase (TaSETup1) that can methylate H3K18 and represses gene expression. Thus, H3K18me1 emerges as an important epigenetic mark which controls gene expression and stage differentiation in Theileria parasites.

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Functional Interplay between Acetylation and Methylation of the RelA Subunit of NF-κB

Molecular and Cellular Biology ◽

10.1128/mcb.01343-09 ◽

2010 ◽

Vol 30 (9) ◽

pp. 2170-2180 ◽

Cited By ~ 81

Author(s):

Xiao-Dong Yang ◽

Emad Tajkhorshid ◽

Lin-Feng Chen

Keyword(s):

Posttranslational Modifications ◽

Transcriptional Activity ◽

Positive Charge ◽

Structural Modeling ◽

Lysine Methylation ◽

Set Domain ◽

Nuclear Activity ◽

The Stability ◽

First Time

ABSTRACT Posttranslational modifications of the RelA subunit of NF-κB, including acetylation and methylation, play a key role in controlling the strength and duration of its nuclear activity. Whether these modifications are functionally linked is largely unknown. Here, we show that the acetylation of lysine 310 of RelA impairs the Set9-mediated methylation of lysines 314 and 315, which is important for the ubiquitination and degradation of chromatin-associated RelA. Abolishing the acetylation of lysine 310 either by the deacetylase SIRT1 or by mutating lysine 310 to arginine enhances methylation. Conversely, enhancing the acetylation of lysine 310 by depleting SIRT1 or by replacing lysine 310 with acetyl-mimetic glutamine inhibits methylation, thereby decreasing ubiquitination, prolonging the stability of chromatin-associated RelA, and enhancing the transcriptional activity of NF-κB. The acetylation of lysine 310 of RelA interferes with its interaction with Set9. Based on structural modeling of the SET domain of Set9 with RelA, we propose that the positive charge of lysine 310 is critical for the binding of RelA to a negatively charged “exosite” within the SET domain of Set9. Together, these findings demonstrate for the first time an interplay between RelA acetylation and methylation and also provide a novel mechanism for the regulation of lysine methylation by acetylation.

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Genome-wide analysis of SET-domain group histone methyltransferases in apple reveals their role in development and stress responses

BMC Genomics ◽

10.1186/s12864-021-07596-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Wenjie Li ◽

Jinjiao Yan ◽

Shicong Wang ◽

Qianying Wang ◽

Caixia Wang ◽

...

Keyword(s):

Stress Responses ◽

Sequence Similarity ◽

Expression Profiles ◽

Expression Patterns ◽

Lysine Methylation ◽

Set Domain ◽

Histone Methyltransferases ◽

Histone Lysine Methylation ◽

Histone Lysine ◽

Genome Wide

Abstract Background Histone lysine methylation plays an important role in plant development and stress responses by activating or repressing gene expression. Histone lysine methylation is catalyzed by a class of SET-domain group proteins (SDGs). Although an increasing number of studies have shown that SDGs play important regulatory roles in development and stress responses, the functions of SDGs in apple remain unclear. Results A total of 67 SDG members were identified in the Malus×domestica genome. Syntenic analysis revealed that most of the MdSDG duplicated gene pairs were associated with a recent genome-wide duplication event of the apple genome. These 67 MdSDG members were grouped into six classes based on sequence similarity and the findings of previous studies. The domain organization of each MdSDG class was characterized by specific patterns, which was consistent with the classification results. The tissue-specific expression patterns of MdSDGs among the 72 apple tissues in the different apple developmental stages were characterized to provide insight into their potential functions in development. The expression profiles of MdSDGs were also investigated in fruit development, the breaking of bud dormancy, and responses to abiotic and biotic stress; the results indicated that MdSDGs might play a regulatory role in development and stress responses. The subcellular localization and putative interaction network of MdSDG proteins were also analyzed. Conclusions This work presents a fundamental comprehensive analysis of SDG histone methyltransferases in apple and provides a basis for future studies of MdSDGs involved in apple development and stress responses.

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The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3

Journal of Experimental Medicine ◽

10.1084/jem.20170856 ◽

2017 ◽

Vol 214 (12) ◽

pp. 3597-3610 ◽

Cited By ~ 15

Author(s):

Chunmei Wang ◽

Qinlan Wang ◽

Xiaoqing Xu ◽

Bin Xie ◽

Yong Zhao ◽

...

Keyword(s):

Innate Immunity ◽

Critical Role ◽

Mass Spectrometry Analysis ◽

Type I ◽

Lysine Methylation ◽

Set Domain ◽

Transcription Activity ◽

Domain 3 ◽

Antiviral Innate Immunity

Lysine methylation is an important posttranslational modification, implicated in various biological pathological conditions. The transcription factor interferon regulatory factor 3 (IRF3) is essential for antiviral innate immunity, yet the mechanism for methylation control of IRF3 activation remains unclear. In this paper, we discovered monomethylation of IRF3 at K366 is critical for IRF3 transcription activity in antiviral innate immunity. By mass spectrometry analysis of IRF3-associated proteins, we identified nuclear receptor–binding SET domain 3 (NSD3) as the lysine methyltransferase that directly binds to the IRF3 C-terminal region through its PWWP1 domain and methylates IRF3 at K366 via its SET domain. Deficiency of NSD3 impairs the antiviral innate immune response in vivo. Mechanistically, NSD3 enhances the transcription activity of IRF3 dependent on K366 monomethylation, which maintains IRF3 phosphorylation by promoting IRF3 dissociation of protein phosphatase PP1cc and consequently promotes type I interferon production. Our study reveals a critical role of NSD3-mediated IRF3 methylation in enhancing antiviral innate immunity.

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