The Tale of Two Domains: Proteomics and Genomics Analysis of SMYD2, A New Histone Methyltransferase

Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Molecular & Cellular Proteomics (Impact Factor: 6.56). 04/2008; 7(3):560-72. DOI: 10.1074/mcp.M700271-MCP200
Source: PubMed


Very little is known about SET- and MYND-containing protein 2 (SMYD2), a member of the SMYD protein family. However, the interest in better understanding the roles of SMYD2 has grown because of recent reports indicating that SMYD2 methylates p53 and histone H3. In this study, we present a combined proteomics and genomics study of SMYD2 designed to elucidate its molecular roles. We report the cytosolic and nuclear interactome of SMYD2 using a combination of immunoprecipitation coupled with high throughput MS, chromatin immunoprecipitation coupled with high throughput MS, and co-immunoprecipitation methods. In particular, we report that SMYD2 interacted with HSP90alpha independently of the SET and MYND domains, with EBP41L3 through the MYND domain, and with p53 through the SET domain. We demonstrated that the interaction of SMYD2 with HSP90alpha enhances SMYD2 histone methyltransferase activity and specificity for histone H3 at lysine 4 (H3K4) in vitro. Interestingly histone H3K36 methyltransferase activity was independent of its interaction with HSP90alpha similar to LSD1 dependence on the androgen receptor. We also showed that the SET domain is required for the methylation at H3K4. We demonstrated using a modified chromatin immunoprecipitation protocol that the SMYD2 gain of function leads to an increase in H3K4 methylation in vivo, whereas no observable levels of H3K36 were detected. We also report that the SMYD2 gain of function was correlated with the up-regulation of 37 and down-regulation of four genes, the majority of which are involved in the cell cycle, chromatin remodeling, and transcriptional regulation. TACC2 is one of the genes up-regulated as a result of SMYD2 gain of function. Up-regulation of TACC2 by SMYD2 occurred as a result of SMYD2 binding to the TACC2 promoter where it methylates H3K4. Furthermore the combination of the SMYD2 interactome with the gene expression data suggests that some of the genes regulated by SMYD2 are closely associated with SMYD2-interacting proteins.

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Available from: Ashraf Madhoun
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    • "SET and MYND domain containing 2 (SMYD2) is one of the SMYD methyltransferase family proteins, containing the SET domain and the MYND domain. SMYD2 methylates histone H3K36 and H3K4, and functions as a transcriptional regulator in cooperation with the Sin3A and HDAC1 histone deacetylase complex [27] [28]. SMYD2 is also known to methylate non-histone protein substrates, including p53 and RB1, and methylated p53 was reported to lose its tumor suppressive function [29] [30]. "
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    • "HsfB1 is targeted to degradation in plants [255] [256] PPARα/β Transcriptional activity is repressed [257] CAR Cytoplasmic retention bound to microtubules [258] [259] PXR Nuclear translocation and transcriptional inactivation are inhibited [260] STATs STAT3 nuclear translocation and IL-6 induction are enhanced. STAT5 activity is favored [219] [261] Nanog Proteasomal degradation is inhibited and pluripotency of stem cells is preserved [262] Oct4 Proteasomal degradation is inhibited and pluripotency of stem cells is preserved [262] p300 Hsp90α is hyperacetylated increasing tumor cell invasiveness [78] Swi/Snf Opens chromatin conformation at the promoter region of heat shock-induced genes [92] Pih1/Tah1 Chromatin remodeling complexes and small nucleolar RNP maturation [143] [144] SmyD Increases levels of methylated H3K4 [108] Bcl6 Preserves BCL-6 stability while it is actively repressing target genes [155] TPR-domain proteins Hop/p60 Intermediates assembly of several client factors. Inhibits methylation of Hsp90α by SmyD [4] [113] FKBP51 Regulates transcriptional activity of steroid receptors. "
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