Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

BRD4 methylation by the methyltransferase SETD6 regulates selective transcription to control mRNA translation.

ABSTRACT: The transcriptional coactivator BRD4 has a fundamental role in transcription regulation and thus became a promising epigenetic therapeutic candidate to target diverse pathologies. However, the regulation of BRD4 by posttranslational modifications has been largely unexplored. Here, we show that BRD4 is methylated on chromatin at lysine-99 by the protein lysine methyltransferase SETD6. BRD4 methylation negatively regulates the expression of genes that are involved in translation and inhibits total mRNA translation in cells. Mechanistically, we provide evidence that supports a model where BRD4 methylation by SETD6 does not have a direct role in the association with acetylated histone H4 at chromatin. However, this methylation specifically determines the recruitment of the transcription factor E2F1 to selected target genes that are involved in mRNA translation. Together, our findings reveal a previously unknown molecular mechanism for BRD4 methylation-dependent gene-specific targeting, which may serve as a new direction for the development of therapeutic applications.

SUBMITTER: Vershinin Z

PROVIDER: S-EPMC8153730 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation.

Project description:Lysine methylation, catalyzed by protein lysine methyltransferases (PKMTs), is a key player in regulating intracellular signaling pathways. However, the role of PKMTs and the methylation of nonhistone proteins during the cell cycle are largely unexplored. In a recent proteomic screen, we identified that the PKMT SETD6 methylates PLK1-a key regulator of mitosis and highly expressed in tumor cells. In this study, we provide evidence that SETD6 is involved in cell cycle regulation. SETD6-deficient cells were observed to progress faster through the different mitotic steps toward the cytokinesis stage. Mechanistically, we found that during mitosis SETD6 binds and methylates PLK1 on two lysine residues: K209 and K413. Lack of methylation of these two residues results in increased kinase activity of PLK1, leading to accelerated mitosis and faster cellular proliferation, similarly to SETD6-deficient cells. Taken together, our findings reveal a role for SETD6 in regulating mitotic progression, suggesting a pathway through which SETD6 methylation activity contributes to normal mitotic pace.

| S-EPMC6347700 | biostudies-literature

PAK4 methylation by the methyltransferase SETD6 attenuates cell adhesion.

Project description:P21-activated kinase 4 (PAK4), a member of serine/threonine kinases family is over-expressed in numerous cancer tumors and is associated with oncogenic cell proliferation, migration and invasion. Our recent work demonstrated that the SET-domain containing protein 6 (SETD6) interacts with and methylates PAK4 at chromatin in mammalian cells, leading to activation of the Wnt/β-catenin signaling pathway. In our current work, we identified lysine 473 (K473) on PAK4 as the primary methylation site by SETD6. Methylation of PAK4 at K473 activates β-catenin transcriptional activity and inhibits cell adhesion. Specific methylation of PAK4 at K473 also attenuates paxillin localization to focal adhesions leading to overall reduction in adhesion-related features, such as filopodia and actin structures. The altered adhesion of the PAK4 wild-type cells is accompanied with a decrease in the migrative and invasive characteristics of the cells. Taken together, our results suggest that methylation of PAK4 at K473 plays a vital role in the regulation of cell adhesion and migration.

| S-EPMC7555502 | biostudies-literature

The METTL5-TRMT112 N<sup>6</sup>-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation.

Project description:Ribosomal RNAs (rRNAs) have long been known to carry chemical modifications, including 2'O-methylation, pseudouridylation, N6-methyladenosine (m6A), and N6,6-dimethyladenosine. While the functions of many of these modifications are unclear, some are highly conserved and occur in regions of the ribosome critical for mRNA decoding. Both 28S rRNA and 18S rRNA carry single m6A sites, and while the methyltransferase ZCCHC4 has been identified as the enzyme responsible for the 28S rRNA m6A modification, the methyltransferase responsible for the 18S rRNA m6A modification has remained unclear. Here, we show that the METTL5-TRMT112 methyltransferase complex installs the m6A modification at position 1832 of human 18S rRNA. Our work supports findings that TRMT112 is required for METTL5 stability and reveals that human METTL5 mutations associated with microcephaly and intellectual disability disrupt this interaction. We show that loss of METTL5 in human cancer cell lines and in mice regulates gene expression at the translational level; additionally, Mettl5 knockout mice display reduced body size and evidence of metabolic defects. While recent work has focused heavily on m6A modifications in mRNA and their roles in mRNA processing and translation, we demonstrate here that deorphanizing putative methyltransferase enzymes can reveal previously unappreciated regulatory roles for m6A in noncoding RNAs.

| S-EPMC8857481 | biostudies-literature

Activity dependent LoNA regulates translation by coordinating rRNA transcription and methylation.

Project description:The ribosome is indispensable for precisely controlling the capacity of protein synthesis. However, how translational machinery is coordinated to meet the translational demands remains elusive. Here, we identify a nucleolar-specific lncRNA (LoNA), its 5' portion binds and sequesters nucleolin to suppress rRNA transcription, and its snoRNA like 3' end recruits and diminishes fibrillarin activity to reduce rRNA methylation. Activity-dependent decrease of LoNA leads to elevated rRNA and ribosome levels, an increased proportion of polysomes, mRNA polysome loading, and protein translation. In addition, transport of ribosomes to synapses is particularly promoted, resulting in increased levels of AMPA/NMDA receptor, enhanced synaptic plasticity, long-term potentiation and consolidated memory. Strikingly, hippocampal LoNA deficiency not only enhances long-term memory in WT mice, but also restores impaired memory function in APP/PS1 transgenic mice. Together, these findings reveal the multifaceted role of LoNA in modulating ribosome biogenesis to meet the translational demands of long-term memory.

| S-EPMC5928123 | biostudies-literature

Peptide inhibition of the SETD6 methyltransferase catalytic activity.

Project description:A large body of evidence accumulating in the past few years indicates the physiological significance of non-histone proteins lysine methylation, catalyzed by protein lysine methyl transferases (PKMTs). Dysregulation of these enzymes was shown to contribute to the development and progression of numerous diseases. SETD6 lysine methylatransferase was recently shown to participate in essential cellular processes, such as the NFkB pathway, oxidative stress and also the Wnt signaling cascade. In order to test the effect of blocking SETD6 catalytic activity, we used the peptide inhibition method, which is considered highly specific and can potentially target almost any protein. We designed a 15 amino acids peptide based on the sequence of the RelA protein (residues 302-316), containing the lysine that is methylated by SETD6. To enable cellular intake, the designed peptide was fused to a cell penetrating peptide (CPP) vp22. The vp22-RelA302-316 peptide showed direct and specific interaction with SETD6 in vitro. This interaction was shown to inhibit SETD6 methyltransferase activity. SETD6 catalytic blockage by the peptide was also observed in cells upon treatment with the vp22-RelA302-316, resulting in induced cellular migration and proliferation. This new insight into the activity of a methylation inhibitory peptide could represent a milestone in the development of therapeutic tools, which can be of use in physiological cases where administration of cell proliferation is required.

| S-EPMC5797019 | biostudies-literature

A novel mRNA 3' untranslated region translational control sequence regulates Xenopus Wee1 mRNA translation.

Project description:Cell cycle progression during oocyte maturation requires the strict temporal regulation of maternal mRNA translation. The intrinsic basis of this temporal control has not been fully elucidated but appears to involve distinct mRNA 3' UTR regulatory elements. In this study, we identify a novel translational control sequence (TCS) that exerts repression of target mRNAs in immature oocytes of the frog, Xenopus laevis, and can direct early cytoplasmic polyadenylation and translational activation during oocyte maturation. The TCS is functionally distinct from the previously characterized Musashi/polyadenylation response element (PRE) and the cytoplasmic polyadenylation element (CPE). We report that TCS elements exert translational repression in both the Wee1 mRNA 3' UTR and the pericentriolar material-1 (Pcm-1) mRNA 3' UTR in immature oocytes. During oocyte maturation, TCS function directs the early translational activation of the Pcm-1 mRNA. By contrast, we demonstrate that CPE sequences flanking the TCS elements in the Wee1 3' UTR suppress the ability of the TCS to direct early translational activation. Our results indicate that a functional hierarchy exists between these distinct 3' UTR regulatory elements to control the timing of maternal mRNA translational activation during oocyte maturation.

| S-EPMC2562724 | biostudies-literature

Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation.

Project description:Transcription and translation are two main pillars of gene expression. Due to the different timings, spots of action, and mechanisms of regulation, these processes are mainly regarded as distinct and generally uncoupled, despite serving a common purpose. Here, we sought for a possible connection between transcription and translation. Employing an unbiased screen of multiple human promoters, we identified a positive effect of TATA box on translation and a general coupling between mRNA expression and translational efficiency. Using a CRISPR-Cas9-mediated approach, genome-wide analyses, and in vitro experiments, we show that the rate of transcription regulates the efficiency of translation. Furthermore, we demonstrate that m6A modification of mRNAs is co-transcriptional and depends upon the dynamics of the transcribing RNAPII. Suboptimal transcription rates lead to elevated m6A content, which may result in reduced translation. This study uncovers a general and widespread link between transcription and translation that is governed by epigenetic modification of mRNAs.

| S-EPMC5388891 | biostudies-literature

The Bin3 RNA methyltransferase targets 7SK RNA to control transcription and translation.

Project description:Bicoid-interacting protein 3 (Bin3) is a conserved RNA methyltransferase found in eukaryotes ranging from fission yeast to humans. It was originally discovered as a Bicoid (Bcd)-interacting protein in Drosophila, where it is required for anterior-posterior and dorso-ventral axis determination in the early embryo. The mammalian ortholog of Bin3 (BCDIN3), also known as methyl phosphate capping enzyme (MePCE), plays a key role in repressing transcription. In transcription, MePCE binds the non-coding 7SK RNA, which forms a scaffold for an RNA-protein complex that inhibits positive-acting transcription elongation factor b, an RNA polymerase II elongation factor. MePCE uses S-adenosyl methionine to transfer a methyl group onto the γ-phosphate of the 5' guanosine of 7SK RNA generating an unusual cap structure that protects 7SK RNA from degradation. Bin3/MePCE also has a role in translation regulation. Initial studies in Drosophila indicate that Bin3 targets 7SK RNA and stabilizes a distinct RNA-protein complex that assembles on the 3'-untranslated region of caudal mRNAs to prevent translation initiation. Much remains to be learned about Bin3/MeCPE function, including how it recognizes 7SK RNA, what other RNA substrates it might target, and how widespread a role it plays in gene regulation and embryonic development.

| S-EPMC3629726 | biostudies-other

Methylation of BRD4 by PRMT1 regulates BRD4 phosphorylation and promotes ovarian cancer invasion.

Project description:Bromodomain-containing protein 4 (BRD4), the major component of bromodomain and extra-terminal domain (BET) protein family, has important functions in early embryonic development and cancer development. However, the posttranslational modification of BRD4 is not well understood. Multiple approaches were used to explore the mechanism of PRMT1-mediated BRD4 methylation and to determine the biological functions of BRD4 and PRMT1 in ovarian cancer. Here we report that BRD4 is asymmetrically methylated at R179/181/183 by PRMT1, which is antagonized by the Jumonji-family demethylase, JMJD6. PRMT1 is overexpressed in ovarian cancer tissue and is a potential marker for poor prognosis in ovarian cancer patients. Silencing of PRMT1 inhibited ovarian cancer proliferation, migration, and invasion in vivo and in vitro. PRMT1-mediated BRD4 methylation was found to promote BRD4 phosphorylation. Compared to BRD4 wild-type (WT) cells, BRD4 R179/181/183K mutant-expressing cells showed reduced ovarian cancer metastasis. BRD4 arginine methylation is also associated with TGF-β signaling. Our results indicate that arginine methylation of BRD4 by PRMT1 is involved in ovarian cancer tumorigenesis. Targeting PRMT1-mediated arginine methylation may provide a novel diagnostic target and an effective therapeutic strategy for ovarian cancer treatment.

| S-EPMC10517134 | biostudies-literature

The methyltransferase PRMT1 regulates γ-globin translation.

Project description:Induction of fetal hemoglobin to overcome adult β-globin gene deficiency is an effective therapeutic strategy to ameliorate human β-hemoglobinopathies. Previous work has revealed that fetal γ-globin can be translationally induced via integrated stress signaling, but other studies have indicated that activating stress may eventually suppress γ-globin expression transcriptionally. The mechanism by which γ-globin expression is regulated at the translational level remains largely unknown, limiting our ability to determine whether activating stress is a realistic therapeutic option for these disorders. In this study, we performed a functional CRISPR screen targeting protein arginine methyltransferases (PRMTs) to look for changes in γ-globin expression in K562 cells. We not only discovered that several specific PRMTs may block γ-globin transcription, but also revealed PRMT1 as a unique family member that is able to suppress γ-globin synthesis specifically at the translational level. We further identified that a non-AUG uORF within the 5' untranslated region of γ-globin serves as a barrier for translation, which is bypassed upon PRMT1 deficiency. Finally, we found that this novel mechanism of γ-globin suppression could be pharmacologically targeted by the PRMT1 inhibitor, furamidine dihydrochloride. These data raise new questions regarding methyltransferase function and may offer a new therapeutic direction for β-hemoglobinopathies.

| S-EPMC7966866 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data