Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Acetylation-Triggered Degradation of MSX1 Impairs Palatal Development

ABSTRACT: Non-syndromic cleft palate (NSCP), a prevalent congenital disorder, arises from dysregulated embryonic palatal fusion, but the posttranslational modifications (PTMs) driving this process remain poorly understood. Here, we identify lysine acetylation as a critical MSX1 proteostasis switch governing embryonic palatal mesenchymal (EPM) cell survival. We demonstrate in vitro and in vivo that MSX1 protein stability regulation by deacetylase SIRT1-catalyzed acetylation underlies EPM apoptosis and palatal fusion. In atRA-induced NSCP models, SIRT1 suppression drives MSX1 hyperacetylation, accelerating proteasomal degradation and culminating in EPM apoptosis. Strikingly, transcriptomic profiling revealed acetylation's exclusive proteostatic role, decoupling MSX1's structural stability from transcriptional activity—a paradigm distinct from classical PTM mechanisms during development. Lentivirus-mediated delivery of deacetylase SIRT1 or the deacetylation mimic MSX1 K139R significantly reduced cleft severity, indicating its preventive and therapeutic potential in humans. Our work establishes the MSX1 acetylation as both a pathogenic driver and druggable target in NSCP, redefining PTM regulation as a central etiological factor in genetic disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316532 | GEO | 2026/04/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

PRMT1-methylated MSX1 phase separates to control palate development

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

Acetylation-Triggered Degradation of MSX1 Impairs Palatal Development

Project description:Acetylation-Triggered Degradation of MSX1 Impairs Palatal Development

| PRJNA1403284 | ENA

Integrated lysine acetylation stoichiometry and proteomics analysis in human cells

Project description:Lysine acetylation is a widespread posttranslational modification that targets a large number of biological pathways. Recent studies reveal that lysine acetylation sites exhibit mainly low stoichiometry. Here we explored three sample preparation methods, the use of detergents for the chemical acetylation reaction in combination with stable and efficient alkylating reagent, to analyze the stoichiometry of acetylation in three human cell lines. We identified and determined the acetylation occupancy in about 1500 protein in each cell line. Lysine acetylation is highly dynamic, we determined variations in the acetylation stoichiometry when nearby residues are phosphorylated. The stoichiometric analysis in combination with quantitative proteomics allowed us to better understand the role of this PTM in different cells. We found that high abundance of the deacetylase SIRT1 correlates with less acetylation occupancy and abundance of ribosomes, proteins involved in ribosome biogenesis, rRNA processing, among others. We confirmed through the inhibition of SIRT1 with EX-527, followed by quantitative proteomics and acetylation stoichiometry analyzes, the negative role of this deacetylase on transcription and translation pathways. In addition, we found that SIRT1 positively regulates several metabolic pathways.

2017-09-12 | PXD005903 | Pride

Integrated lysine acetylation stoichiometry and proteomics analysis in human cells

2017-11-09 | MSV000081704 | MassIVE

The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells

Project description:Selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program in satellite cells To establish the role of the deacetylase SIRT1 in skeletal muscle we examined the genome wide distribution of H4K16ac in quiescent (FI) and proliferating (Cul) satellite cells isolated from WT mice (C57Bl/6 background) and SIRT1mKO (generated via breeding of Pax7cre/+ knock-in mice with mice containing the floxed exon 4 SIRT1 allele). We also analyzed the distribution of SIRT1 in quiescent and proliferating FACS isolated WT satellite cells (two replicates). We generated the mRNA profiles (at least two replicate for each experiment) of FACS isolated quiescent, proliferating and differentiating (1 day in differentiation medium) satellite cells of WT mice and SIRT1mKO. The selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program.

2015-01-30 | E-GEOD-64379 | biostudies-arrayexpress

MSX1-induced neural crest-like phenotype in human melanocytes

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

RNAseq comparison of gene expression profiles in Hand2-Cre driven Msx1/Msx2 double conditional mutant and control mouse embryonic mandible

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.

2024-01-10 | GSE222566 | GEO

Loss of p130Cas impairs palatal mesenchymal expansion and causes cleft palate

Project description:Palatogenesis is a complex developmental process requiring coordinated growth, elevation, and fusion of the palatal shelves. Disruption of these events results in cleft palate, one of the most common congenital craniofacial anomalies. p130Crk-associated substrate (p130Cas) is an adaptor protein involved in integrin-mediated signaling and cytoskeletal regulation; however, its roles in late embryonic development remain poorly understood because global p130Cas-deficiency leads to early embryonic lethality. In this study, we used tamoxifen-inducible conditional knockout mice to investigate the function of p130Cas during palatal development. Conditional deletion of p130Cas resulted in cleft palate characterized by impaired horizontal growth of the palatal shelves. Reduced mesenchymal cell proliferation within the palatal shelves was confirmed by Ki-67 immunostaining and EdU incorporation. Consistently, primary mouse embryonic palatal mesenchymal (MEPM) cells derived from p130Cas-deficient embryos exhibited impaired proliferation and migration in vitro. In contrast, epithelial-specific deletion of p130Cas did not result in cleft palate, indicating that p130Cas function in the palatal mesenchyme is critical for normal palatal development. Together, these findings identify p130Cas as an important regulator of palatal mesenchymal expansion during secondary palatogenesis. Impaired proliferative growth of palatal mesenchyme likely underlies the developmental basis of cleft palate in this model.

2026-04-07 | GSE326799 | GEO

Global quantitative proteomics analysis reveals the downstream signaling networks of Msx1 and Msx2 in skeletal muscle development

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.

2023-07-20 | PXD026944 | Pride

p63 spatio-temporal control of cleft palate

Project description:Cleft palate is a common congenital anomaly with a live birth prevalence estimated to be 1:2500 live births, that results from failure of growth, elevation, adhesion and/or fusion of the palatal shelves during embryogenesis. Mutations in the gene encoding the transcription factor p63 result in cleft palate in humans and mice. To study the roles of P63 in periderm migration and medial edge epithelia in mice sub-mucous cleft palate, ÎNp63alpha was ectopically expressed in the palatal epithelia using a transgenic approach.

2017-06-12 | E-MTAB-5289 | biostudies-arrayexpress

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