PRMT1-methylated MSX1 phase separates to control palate development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1205740 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31874112_1.fastq.gz | Fastqsanger.gz | |||
| SRR31874112_2.fastq.gz | Fastqsanger.gz | |||
| SRR31874113_1.fastq.gz | Fastqsanger.gz | |||
| SRR31874113_2.fastq.gz | Fastqsanger.gz | |||
| SRR31874114_1.fastq.gz | Fastqsanger.gz |
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Project description:Little is known about the regulation and function of liquid‒liquid phase separation (LLPS) in craniofacial developmental disorders, where Msh homeobox 1 (MSX1) and protein arginine methyltransferase 1 (PRMT1) are two important regulators. MSX1 mutations are associated with human cleft palate, the most common craniofacial birth defect. Here, we show that MSX1 LLPS, regulated by PRMT1-catalyzed methylation, is a vertebrate-conserved mechanism underlying the proliferation of embryonic palatal mesenchymal cells (EPMs) and palatal fusion. MSX1 LLPS is triggered by its N-terminal intrinsically disordered protein region (IDR) and regulated by PRMT1-catalyzed methylation, specifically asymmetric dimethylation of arginine (R). Biochemically, PRMT1 methylates MSX1 by dimethylating the residues R150 and R157 in the MSX1 IDR. Physiochemically, the R157 to serine (R157S) mutant, R150S mutant, and hypomethylated MSX1 under PRMT1 deficiency consistently cause abnormal MSX1 LLPS to form less dynamic gel-like condensates. PRMT1 and its methylation target R residues in MSX1 are conserved in vertebrates, from zebrafish to humans. Phenotypically, less dynamic gel-like condensates formed by abnormal MSX1 LLPS cause EPM proliferation defects and cleft palate.In this study, rna-seq was used to reveal the differences between the effects of Msx1 and its mutants on hepm cells. Our findings provide a new paradigm for further exploration of LLPS underlying genetic disorders for future innovation of genetic disorder treatment by direct modulation of LLPS.
2025-01-07 | GSE285740 | GEO
Project description:Little is known about the regulation and function of phase separation in craniofacial developmental disorders. MSX1 mutations are associated with human cleft palate, the most common craniofacial birth defect. Here, we show that MSX1 phase separation is a vertebrate-conserved mechanism underlying embryonic palatal fusion. Notably, MSX1 phase separation is triggered by its intrinsically disordered protein region (IDR) and regulated by PRMT1-catalyzed methylation, specifically asymmetric dimethylation of arginine in the MSX1 IDR including R150 and R157. Hypomethylated MSX1 due to methylation site mutations and PRMT1 deficiency consistently leads to abnormal MSX1 phase separation to form less dynamic gel-like condensates, resulting in proliferation defects of embryonic palatal mesenchymal cells and cleft palate. Besides, high frequency mutations in the MSX1 IDR, especially R157S, have been identified in humans with cleft palate. Overall, we reveal the function and regulatory pathway of MSX1 phase separation as a conserved mechanism underlying cleft palate, providing a proof-of-concept example of a phenotype-associated phase separation mechanism associated with craniofacial developmental disorders.
| S-EPMC11754605 | biostudies-literature
Project description:We report that neural crest-specific deletion of Prmt1 caused craniofacial malformations including cleft palate.
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Project description:C/EBPα is an essential transcription factor involved in regulating the expression or function of certain cell-cycle regulators. However, little is known about the role of methylation in regulating the antiproliferation activity of C/EBPα. Here, we report that knockdown of protein arginine methyltransferases 1 (PRMT1) leads to cellular growth arrest accompanied by a decrease in Cyclin D1 gene expression in breast cancer cells. Furthermore, we reveal that C/EBPα is methylated by PRMT1 at three arginine residues (R35, R156, and R165), which impairs the interaction of C/EBPα with HDAC3 and modulates the transcription activity of C/EBPα and Cyclin D1 gene expression. PRMT1 is upregulated in human breast cancer, and elevated PRMT1 is correlated with cancer malignancy. Most importantly, a specific inhibitor of PRMT1 significantly impedes the growth of cancer cells from triple-negative breast cancer patients. Our data demonstrate that high expression of PRMT1 promotes the expression of Cyclin D1 through methylation of C/EBPα to interfere with the repressive function of HDAC3, which leads to rapid growth of tumor cells during the pathogenesis of breast cancer. This evidence that PRMT1 mediates C/EBPα methylation sheds light on a novel therapeutic pathway for breast cancer.
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Project description:PRMT1 is thought to be responsible for the majority of PRMT activity in Toxoplasma gondii, but its exact function is unknown. We generated T. gondii mutants lacking PRMT1 (∆prmt1) by deletion of the PRMT1 gene. ∆prmt1 parasites exhibit morphological defects during cell division and grow slowly, and this phenotype reverses in the complemented strain ∆prmt::PRMT1mRFP. PRMT1 localizes primarily in the cytoplasm with enrichment at the centrosome, and the strain lacking PRMT1 is unable to segregate progeny accurately. Unlike wild-type and complemented parasites, ∆prmt1 parasites have abnormal daughter buds, perturbed centrosome stoichiometry, and loss of synchronous replication. Whole genome expression profiling demonstrated differences in expression of cell cycle regulated genes in ∆prmt1 relative to the complemented ∆prmt1::PRMT1mRFP and parental wild-type strains, but these changes did not correlate with a specific block in cell cycle. Although PRMT1’s primary biological function was previously proposed to be methylation of histones, our genetic studies suggest that the most critical function of PRMT1 is within the centrosome as a regulator of daughter cell counting to assure the proper replication of the parasite. RNA samples were isolated in triplicates from RH-hxgprt parent strain (W), PRMT1 knockout (K) strain and PRMT1 knockout strain complemented with RFP-tagged PRMT1 protein (C). Parasites were grown for 32h at 37C. Samples were hybridized to the Toxoplasma gondii Affymetrix microarray (ToxoGeneChip: http://ancillary.toxodb.org/docs/Array-Tutorial.html). Hybridization data was preprocessed with Robust Multi-array Average (RMA) and normalized using per chip and per gene median polishing and analyzed using the software package GeneSpring GX (Agilent Technologies).
2015-09-18 | E-GEOD-73177 | biostudies-arrayexpress
Project description:The homeoprotein Msx1 and Msx2 involved in normal skeletal muscle development and also contribute to muscle defects if altered during development. Deciphering the downstream signaling networks of Msx1 and Msx2 in myoblasts differentiation will help us to understand the molecular events that contribute to muscle defects. The objective of this study was to evaluate the proteomics characteristics in Msx1 and Msx2 mediated myoblasts differentiation, using isobaric tags for the relative and absolute quantification labelling technique (iTRAQ). The results showed that 1535 proteins with quantitative information were obtained. Volcano plots illustrated, in undifferentiated stage, 32 common downstream regulatory proteins for Msx1 and Msx2, 39 specific regulatory proteins for Msx1, and 13 specific for Msx2. While, in differentiated stage, 17 common downstream regulatory proteins for Msx1 and Msx2, 10 specific regulatory proteins for Msx1, and 21 specific for Msx2. Gene ontology, KEGG pathway and protein-protein interaction networks analyses revealed these proteins primarily associated with Arginine and proline metabolism, Glycolysis/Gluconeogenesis, Fatty acid degradation, Metabolism of xenobiotics by cytochrome P450 and Apoptosis. In addition, our data shows Acta1 was probably a core of the downstream regulatory networks of Msx1 and Msx2 in skeletal muscle development. The findings will help us to understand the molecular roles of Msx1 and Msx2 during muscle development as well as regeneration, and to understand the molecular events that contribute to muscle defects.
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Project description:Msh homeobox 1 (MSX1) is a transcription factor implicated in neural crest specification. Ectopic expression of MSX1 reprograms mature melanocytes into a neural crest-like state as a single factor. MSX1-reprogrammed melanocytes lose pigmentation and become multipotent. To identify immediate targets of MSX1, we generated a tetracycline-inducible system (Tet-ON) in order to express MSX1 in primary melanocytes (iMSX1) in a clean and rapid way starting at defined time points and perform a global gene expression analysis.
2016-09-30 | GSE56957 | GEO
Project description:The mandible of the jawed vertebrate is derived from the mandibular process of the first pharyngeal arch of the early embryo. The first pharyngeal arch consists of cells from all three germ layers, with the neural crest giving rise to all the skeletal elements of the mandible. The correct patterning of the neural crest cells by spatially and temporally controlled expression of various transcription factors during mandible development is crucial for the proper morphogenesis of the lower jaw. Msx family genes encode transcription factors which contain the conserved homeodomain. Among the three members of Msx genes, Msx1 and Msx2 are expressed in the neural crest and epithelium of distal mandibular process during early embryonic development with partially overlapped expression patterns. Msx1-/- mouse embryos develop multiple craniofacial developmental defects including tooth agenesis, cleft palate, and hypoplastic mandible. Although no jaw defects were observed in Msx2-/- mouse embryos, Msx1-/-Msx2-/- mouse embryos exhibit significantly severer mandibular defects compared to Msx1-/- mouse embryos, suggesting a partial functional redundancy between the two genes in mandible development. Besides the direct roles of Msx1 and Msx2 in the development of the mandibular neural crest, the phenotypes of Msx1-/-Msx2-/- may also contributed by secondary impacts from defective pre-migrative neural crest and non-neural crest tissues. Here we performed the gene expression profiling by RNA-seq in the distal mandibular processes of Msx1f/f;Msx2f/f;Hand2-Cre and Msx1f/+;Msx2f/f;Hand2-Cre embryos at E10.75, the former developed distally truncated mandible at later stages while the latter served as morphologically normal littermate control. Comparing the gene expression profiles of the two will give us insight into the functions of Msx1 and Msx2 expressed in mandibular neural crest cells in the development of the mandible.
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