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TDRD3 is an effector molecule for arginine methylated histone marks

ABSTRACT: Specific sites of histone tail methylation are associated with transcriptional activity at gene loci. These methyl-marks are interpreted by effector molecules, which harbor protein domains that bind the methylated motifs and facilitate either active or inactive states of transcription. CARM1 and PRMT1 are transcriptional coactivators that deposit H3R17me2a and H4R3me2a marks, respectively. We used a protein domain microarray approach to identify the tudor domain-containing protein TDRD3 as a “reader” of these marks. Importantly, TDRD3 itself is a transcriptional coactivator. This coactivator activity requires an intact tudor domain. TDRD3 is recruited to an estrogen responsive element in a CARM1-dependent manner. Furthermore, ChIP-seq analysis of TDRD3 reveals that it is predominantly localized to transcriptional start site. Thus, TDRD3 is an effector molecule that promotes transcription by binding methylarginine marks on histone tails.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22612 | GEO | 2011/01/06

SECONDARY ACCESSION(S): PRJNA128353

REPOSITORIES: GEO

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TDRD3 is an effector molecule for arginine methylated histone marks

Project description:Specific sites of histone tail methylation are associated with transcriptional activity at gene loci. These methyl-marks are interpreted by effector molecules, which harbor protein domains that bind the methylated motifs and facilitate either active or inactive states of transcription. CARM1 and PRMT1 are transcriptional coactivators that deposit H3R17me2a and H4R3me2a marks, respectively. We used a protein domain microarray approach to identify the tudor domain-containing protein TDRD3 as a “reader” of these marks. Importantly, TDRD3 itself is a transcriptional coactivator. This coactivator activity requires an intact tudor domain. TDRD3 is recruited to an estrogen responsive element in a CARM1-dependent manner. Furthermore, ChIP-seq analysis of TDRD3 reveals that it is predominantly localized to transcriptional start site. Thus, TDRD3 is an effector molecule that promotes transcription by binding methylarginine marks on histone tails. ChIP seq analysis of TDRD3 in MCF7 cells

2011-01-06 | E-GEOD-22612 | biostudies-arrayexpress

TDRD3 promotes DHX9 chromatin recruitment and R-loop resolution

Project description:R-loops, which consist of a DNA/RNA hybrid and a displaced single-stranded DNA (ssDNA), are increasingly recognized as critical regulators of chromatin biology. R-loops are particularly enriched at gene promoters, where they play important roles in regulating gene expression. However, the molecular mechanisms that control promoter-associated R-loops remain unclear. The epigenetic “reader” Tudor domain-containing protein 3 (TDRD3), which recognizes methylarginine marks on histones and on the C-terminal domain of RNA polymerase II, was previously shown to recruit DNA topoisomerase 3B (TOP3B) to relax negatively supercoiled DNA and prevent R-loop formation. Here, we further characterize the function of TDRD3 in R-loop metabolism and introduce the DExH-box helicase 9 (DHX9) as a novel interaction partner of the TDRD3/TOP3B complex. TDRD3 directly interacts with DHX9 via its Tudor domain. This interaction is important for recruiting DHX9 to target gene promoters, where it resolves R-loops in a helicase activity-dependent manner to facilitate gene expression. Additionally, TDRD3 also stimulates the helicase activity of DHX9. This stimulation relies on the OB-fold of TDRD3, which likely binds the ssDNA in the R-loop structure. Thus, DHX9 functions together with TOP3B to suppress promoter-associated R-loops. Collectively, these findings reveal new functions of TDRD3 and provide important mechanistic insights into the regulation of R-loop metabolism.

2021-06-26 | GSE178905 | GEO

A hypermethylation strategy utilized by enhancer-bound CARM1 to promote estrogen receptor a-dependent transcriptional activation and breast carcinogenesis (ChIP-Seq)

Project description:While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their roles in carcinogenesis, particularly in estrogen receptor alpha (ERa)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) due to its high expression and the associated poor prognosis in ERa-positive breast cancers. We first uncovered the chromatin-binding landscape and transcriptional targets of CARM1 in the presence of estrogen in ERa-positive breast cancer cells employing genomic and transcriptomics approaches. CARM1 was found to be predominantly and specifically recruited to ERa-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced gene transcriptional activation in response to estrogen. Global mapping of CARM1 substrates revealed that CARM1 methylates a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor signaling, chromatin organization, chromatin remodeling and others. Intriguingly, a number of proteins were hypermethylated exclusively by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor domain-containing 3 (TDRD3), to ensure the full activation of estrogen/ERa target genes. In consistent with its critical role in estrogen-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERa-positive breast cancer cells in vitro and tumor growth in mice. Taken together, our study uncovered a “hypermethylation” strategy utilized by CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.

2020-03-31 | GSE124448 | GEO

A hypermethylation strategy utilized by enhancer-bound CARM1 to promote estrogen receptor a-dependent transcriptional activation and breast carcinogenesis (RNA-seq)

2020-01-17 | GSE124447 | GEO

Evolving Spindlin1 Small Molecule Inhibitors Using Protein Microarrays

Project description:Using a library of tagged UNC1215 analogs, we screened a protein domain microarray of methyl-lysine effector molecules to rapidly detect compounds with novel binding profiles. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor domain-containing protein Spindlin1 (SPIN1). Structural studies revealed that the symmetric nature of EML405 allows it to simultaneously engage two of SPIN1’s Tudor domains, and also facilitated the rational synthesis of more selective SPIN1 inhibitor (EML631). The EML631 compound engages SPIN1 in cells, blocks its ability to “read” H3K4me3 marks, and inhibits its transcriptional coactivator activity.

2017-04-17 | GSE92547 | GEO

Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity [PRO-Seq]

Project description:To study the post-transcriptional regulation of Tdrd3 in the brain.

2023-06-23 | GSE223566 | GEO

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response

Project description:Physiologically, Notch signal transduction plays a pivotal role in differentiation; pathologically, Notch signaling contributes to the development of cancer. Transcriptional activation of Notch target genes involves cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD), and NICD migration into the nucleus and assembly of a coactivator complex. Posttranslational modifications of the NICD are important for its transcriptional activity and protein turnover. Deregulation of Notch signaling and stabilizing mutations of Notch1 have been linked to leukemia development. We found that the methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1; also known as PRMT4) methylated NICD at five conserved arginine residues within the C-terminal transactivation domain. CARM1 physically and functionally interacted with the NICD-coactivator complex and was found at gene enhancers in a Notch-dependent manner. Although a methylation-defective NICD mutant was biochemically more stable, this mutant was biologically less active as measured with Notch assays in embryos of Xenopus laevis and Danio rerio. Mathematical modeling indicated that full but short and transient Notch signaling required methylation of NICD. Analysis of gene expression upon inactivation and activation of Notch signaling in Beko cells. Beko cells were treated with DAPT or DMSO for 24h. Or Beko cells were infected with a DNMAML-ER or Notch1-ER fusion protein. After Selection cells were treated with 4-OHT (Tamoxifen) or Ethanol for 48h.

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Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity [RNA-Seq]

Project description:To study the function of Tdrd3 in the brain.

2023-06-23 | GSE223567 | GEO

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response

2015-03-26 | GSE62528 | GEO

Expression profiling of murine neonatal lung tissue from Carm1 knockouts and wild type controls

Project description:Coactivator associated arginine methyltransferase I (CARM1, also known as Protein aRginine MethylTransferase 4, or PRMT4) regulates gene expression by multiple mechanisms including methylation of histones and coactivation of steroid receptor transcription. Mice lacking CARM1 are smaller than their littermates, fail to breath, and die shortly after birth, demonstrating the critical role of CARM1 in development.We performed gene expression analysis to identify genes that are responsible for hyperproliferaion in CARM1 knockout lung. RNA extracted from murine lung at E18.5 with carm1 knockouts and wild type controls was hybridised to Affymetrix mouse430.2 GeneChips to identify differentially expressed genes in the disease state.

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