Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA401903 | ENA |
REPOSITORIES: ENA
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Project description:CHD7, an ATP-dependent chromatin remodeler, is disrupted in CHARGE syndrome, an autosomal dominant condition characterized by variably penetrant abnormalities in craniofacial, cardiac, and neuronal tissues. The inner ear is uniquely sensitive to CHD7 levels and is the most commonly affected organ in individuals with CHARGE. Interestingly, up- or down-regulation of retinoic acid (RA) signaling during embryogenesis leads to developmental defects similar to those in CHARGE syndrome, suggesting CHD7 and RA share target genes or signaling pathways. Here, we report that CHD7 and retinoic acid receptor (RAR) do not directly interact, and that RA induces rapid neuronal differentiation of human SH-SY5Y neuroblastoma cells without affecting CHD7 levels. Instead, we provide evidence that CHD7 directly regulates expression of Aldh1a3, which encodes an RA synthetic enzyme, and that loss of Aldh1a3 partially rescues Chd7-mutant mouse inner ear defects, indicating that ALDH1A3 acts with CHD7 in a common genetic pathway to regulate inner ear development.
2020-08-30 | GSE103288 | GEO
Project description:Inner ear morphogenesis requires tightly regulated epigenetic and transcriptional control of gene expression. CHD7, an ATP-dependent chromodomain helicase DNA-binding protein, and SOX2, an SRY-related HMG box pioneer transcription factor, are known to contribute to vestibular and auditory system development, but their genetic interactions in the ear have not been explored. Here, we analyzed inner ear development and the transcriptional regulatory landscapes in mice with variable dosage of Chd7 and/or Sox2. We show that combined haploinsufficiency for Chd7 and Sox2 results in reduced otic cell proliferation, severe malformations of semicircular canals, and shortened cochlea with ectopic hair cells. Examination of mice with conditional, inducible Chd7 loss by Sox2CreER reveals a critical period (~E9.5) of susceptibility in the inner ear to combined Chd7 and Sox2 loss. Data from genome-wide RNA-sequencing and CUT&Tag studies in the otocyst show that CHD7 regulates Sox2 expression and acts early in a gene regulatory network to control expression of key otic patterning genes, including Pax2 and Otx2. CHD7 and SOX2 directly bind independently and cooperatively at transcription start sites and enhancers to regulate otic progenitor cell proliferation and function. Together, our findings reveal essential roles for Chd7 and Sox2 in the early inner ear and may be applicable for CHD7 and SOX2 related syndromic and other forms of hearing or balance disorders.
2024-03-01 | GSE239361 | GEO
Project description:Inner ear morphogenesis requires tightly regulated epigenetic and transcriptional control of gene expression. CHD7, an ATP-dependent chromodomain helicase DNA-binding protein, and SOX2, an SRY-related HMG box pioneer transcription factor, are known to contribute to vestibular and auditory system development, but their genetic interactions in the ear have not been explored. Here, we analyzed inner ear development and the transcriptional regulatory landscapes in mice with variable dosage of Chd7 and/or Sox2. We show that combined haploinsufficiency for Chd7 and Sox2 results in reduced otic cell proliferation, severe malformations of semicircular canals, and shortened cochlea with ectopic hair cells. Examination of mice with conditional, inducible Chd7 loss by Sox2CreER reveals a critical period (~E9.5) of susceptibility in the inner ear to combined Chd7 and Sox2 loss. Data from genome-wide RNA-sequencing and CUT&Tag studies in the otocyst show that CHD7 regulates Sox2 expression and acts early in a gene regulatory network to control expression of key otic patterning genes, including Pax2 and Otx2. CHD7 and SOX2 directly bind independently and cooperatively at transcription start sites and enhancers to regulate otic progenitor cell proliferation and function. Together, our findings reveal essential roles for Chd7 and Sox2 in the early inner ear and may be applicable for CHD7 and SOX2 related syndromic and other forms of hearing or balance disorders.
2024-03-01 | GSE239362 | GEO
Project description:Mutations in the chromatin remodeling enzyme CHD7 cause CHARGE syndrome, which affects multiple organs including the inner ear. We investigated how CHD7 mutations affect otic development in human inner ear organoids. We found loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells, which can be explained by dysregulation of key otic development-associated genes in mutant otic progenitors. Further analysis of the mutant otic progenitors suggested that CHD7 can regulate otic genes through a chromatin remodeling-independent mechanism. Results from transcriptome profiling of hair cells revealed disruption of deafness gene expression as a potential underlying mechanism of CHARGE-associated sensorineural hearing loss. Notably, co-differentiating CHD7 knockout and wild-type cells in chimeric organoids partially rescued mutant phenotypes by restoring otherwise severely dysregulated otic genes. Taken together, our results suggest that CHD7 plays a critical role in regulating human otic lineage differentiation and deafness gene expression.
2022-07-21 | GSE208585 | GEO
Project description:Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs potentially regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). Accordingly, potent and selective inhibitors of key ALDHs may represent a novel CSC-directed treatment paradigm for ALDH+ cancer types. Of the many ALDH isoforms, we and others have implicated the elevated expression of ALDH1A3 in mesenchymal glioma stem cells (MES GSCs) as a target for the development of novel therapeutics. To this end, we used our structure of human ALDH1A3 combined with in silico modeling to identify a selective, active-site inhibitor of ALDH1A3. The lead compound, MCI-INI-3, is a selective competitive inhibitor of human ALDH1A3 and shows poor inhibitory effect on the structurally related isoform ALDH1A1. Mass spectrometry-based cellular thermal shift analysis revealed that ALDH1A3 is the primary binding protein for MCI-INI-3 in MES GSC lysates. The inhibitory effect of MCI-INI-3 on retinoic acid biosynthesis is comparable with that of ALDH1A3 knockout, suggesting that effective inhibition of ALDH1A3 is achieved with MCI-INI-3. Further development is warranted to characterize the role of ALDH1A3 and retinoic acid biosynthesis in glioma stem cell growth and differentiation.
2022-02-15 | PXD028125 | Pride
Project description:The T-box transcription factor Tbx1 is expressed in the otic vesicle and surrounding periotic mesenchyme during inner ear development. Mesenchymal Tbx1 is essential for inner ear development, with conditional mutants displaying defects in both auditory and vestibular systems. We have previously identified reduced expression of retinoic acid metabolic genes in the periotic mesenchyme of mesoderm conditional Tbx1 mutants, using the T-Cre mouse line, implicating retinoic acid in mesenchymal-epithelial signaling downstream of Tbx1 in the periotic mesenchyme. In order to identify downstream effectors of mesenchymal-epithelial signaling downstream of mesenchymal Tbx1, we have utilized a gene profiling approach comparing embryonic day 11.5 otic vesicle tissue from T-Cre-mediated conditional Tbx1 mutants (Mest-KO) and conditional heterozygous control litter mates (control).
2013-01-01 | GSE34064 | GEO
Project description:The T-box transcription factor Tbx1 is expressed in the otic vesicle and surrounding periotic mesenchyme during inner ear development. Mesenchymal Tbx1 is essential for inner ear development, with conditional mutants displaying defects in both auditory and vestibular systems. We have previously identified reduced expression of retinoic acid metabolic genes in the periotic mesenchyme of mesoderm conditional Tbx1 mutants, using the T-Cre mouse line, implicating retinoic acid in mesenchymal-epithelial signaling downstream of Tbx1 in the periotic mesenchyme. In order to identify downstream effectors of mesenchymal-epithelial signaling downstream of mesenchymal Tbx1, we have utilized a gene profiling approach comparing embryonic day 12.5 periotic tissue from T-Cre-mediated conditional Tbx1 mutants (Mest-KO) and conditional heterozygous control litter mates (control).
2013-01-01 | GSE34062 | GEO
Project description:Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs potentially regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). ALDH1A3 is the dominant isomer of the ALDH gene family in Mesenchymal subtype of GSC cells and is highly upregulated compared to other subtype of GSCs. ALDH1A3 is an important enzyme in the synthesis of Retinoic Acid, which regulates various downstream pathways and the transcription of numerous genes. Microarray analysis of the GSCs before or after depletion of ALDH1A3 provides important information to determine the genes regulated by ALDH1A3 in the mesenchymal subtype of GSCs. We used microarrays to analyze the transcriptome change after the depletion of ALDH1A3 in GSC-326 cells that express very high levels of ALDH1A3.
2021-10-07 | GSE185463 | GEO
Project description:The T-box transcription factor Tbx1 is expressed in the otic vesicle and surrounding periotic mesenchyme during inner ear development. Mesenchymal Tbx1 is essential for inner ear development, with conditional mutants displaying defects in both auditory and vestibular systems. We have previously identified reduced expression of retinoic acid metabolic genes in the periotic mesenchyme of mesoderm conditional Tbx1 mutants, using the T-Cre mouse line, implicating retinoic acid in mesenchymal-epithelial signaling downstream of Tbx1 in the periotic mesenchyme. In order to identify downstream effectors of mesenchymal-epithelial signaling downstream of mesenchymal Tbx1, we have utilized a gene profiling approach comparing embryonic day 11.5 otic vesicle tissue from T-Cre-mediated conditional Tbx1 mutants (Mest-KO) and conditional heterozygous control litter mates (control). E11.5 T-Cre-mediated conditional Tbx1 mutants (Mest-KO) and control (T-Cre conditional Tbx1 heterozygotes) embryos were microdissected to isolate the otic vesicle. Left and right ears from 3 embryos of the same genotype were pooled for each chip.
2013-01-01 | E-GEOD-34064 | biostudies-arrayexpress
Project description:The T-box transcription factor Tbx1 is expressed in the otic vesicle and surrounding periotic mesenchyme during inner ear development. Mesenchymal Tbx1 is essential for inner ear development, with conditional mutants displaying defects in both auditory and vestibular systems. We have previously identified reduced expression of retinoic acid metabolic genes in the periotic mesenchyme of mesoderm conditional Tbx1 mutants, using the T-Cre mouse line, implicating retinoic acid in mesenchymal-epithelial signaling downstream of Tbx1 in the periotic mesenchyme. In order to identify downstream effectors of mesenchymal-epithelial signaling downstream of mesenchymal Tbx1, we have utilized a gene profiling approach comparing embryonic day 12.5 periotic tissue from T-Cre-mediated conditional Tbx1 mutants (Mest-KO) and conditional heterozygous control litter mates (control). E12.5 T-Cre-mediated conditional Tbx1 mutants (Mest-KO) and control (T-Cre conditional Tbx1 heterozygotes) embryos were microdissected to isolate the otic vesicle and surrounding periotic mesenchyme. Left and right tissue from each individual embryo was pooled, and 5 control and 5 mutant embryos were analyzed on individual microarrays using Affymetrix Mouse Gene ST 1.0 chips.
2013-01-01 | E-GEOD-34062 | biostudies-arrayexpress