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RNA-Seq analysis of Gtf2ird1 knockout epidermal tissue provides potential insights into molecular mechanisms underpinning Williams-Beuren syndrome

ABSTRACT: Using a targeted Gtf2ird1 knockout mouse, we employed massively-parallel sequencing of mRNA (RNA-Seq) to understand changes in the transcriptional landscape associated with inactivation of Gtf2ird1 in lip tissue. We found widespread dysregulation of genes including differential expression of 78 transcription factors or coactivators, several involved in organ development including Hey1, Myf6, Myog, Dlx2, Gli1, Gli2, Lhx2, Pou3f3, Sox2, and Foxp3. We also found that the absence of GTF2IRD1 is associated with increased expression of genes involved in cellular proliferation, including growth factors consistent with the observed phenotype of extreme thickening of the epidermis. At the same time, there was a decrease in the expression of genes involved in other signalling mechanisms, including the Wnt pathway, indicating dysregulation in the complex networks necessary for epidermal differentiation and facial skin patterning. Several of the differentially expressed genes have known roles in both tissue development and neurological function, such as the transcription factor Lhx2 which regulates several genes involved in both skin and brain development.

ORGANISM(S): Mus musculus

PROVIDER: GSE81082 | GEO | 2016/08/03

SECONDARY ACCESSION(S): PRJNA320433

REPOSITORIES: GEO

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Similar Datasets

RNA-Seq analysis of Gtf2ird1 knockout epidermal tissue provides potential insights into molecular mechanisms underpinning Williams-Beuren syndrome

Project description:Using a targeted Gtf2ird1 knockout mouse, we employed massively-parallel sequencing of mRNA (RNA-Seq) to understand changes in the transcriptional landscape associated with inactivation of Gtf2ird1 in lip tissue. We found widespread dysregulation of genes including differential expression of 78 transcription factors or coactivators, several involved in organ development including Hey1, Myf6, Myog, Dlx2, Gli1, Gli2, Lhx2, Pou3f3, Sox2, and Foxp3. We also found that the absence of GTF2IRD1 is associated with increased expression of genes involved in cellular proliferation, including growth factors consistent with the observed phenotype of extreme thickening of the epidermis. At the same time, there was a decrease in the expression of genes involved in other signalling mechanisms, including the Wnt pathway, indicating dysregulation in the complex networks necessary for epidermal differentiation and facial skin patterning. Several of the differentially expressed genes have known roles in both tissue development and neurological function, such as the transcription factor Lhx2 which regulates several genes involved in both skin and brain development. mRNA sequencing of lip tissue from 3 wild type mice (WT) and 3 Gtf2ird1 knockout mice generated by deep sequencing using Illumina HiSeq 2000 platform at the Ramaciotti Centre for Genomics UNSW.

2016-08-03 | E-GEOD-81082 | biostudies-arrayexpress

Gtf2i and Gtf2ird1 E13.5 whole brain ChIP-seq and RNA-seq

Project description:HetxHet breeding pairs for the Gtf2i/Gtf2ird1 double mutants and Gtf2ird1 were set up for timed breedings. E13.5 embyros of WT, HET, and HOM mutants (n=3 for each genotype and each cross), were used for RNA-seq. Similar breedings were done for ChIP-seq. The ChIP-seq WT controls were E13.5 embyros from WT FVB/ANTJ x FVB/ANTJ and compared to HOM Gtf2i/Gtf2ird1 double mutatns and HOM Gtf2ird1 single mutants. There were n=3 WT and n=3 hom Gtf2ird1 single mutants for Gtf2ird1 ChIP-seq. There were n=4 WT and n=4 hom Gtf2i/Gtf2ird1 double mutants for Gtf2i ChIP-seq. Each genotype had the sample matched input control along with ChIP sample.

2020-11-11 | GSE138234 | GEO

GTF2IRD1 regulates cone gene expression to maintain the topology and function of retinal cone photoreceptors

Project description:The mechanisms that specify cone photoreceptor cell-fate to short-wave-sensitive (S) versus medium-wave-sensitive (M) cones and maintain their nature are not fully understood. Here we report the importance of the GTF2IRD1 transcription factor in maintaining M cone cell identity and function. In the mouse, GTF2IRD1 is expressed in cell-fate determined photoreceptors at postnatal day 10. GTF2IRD1 binds to the enhancer and promoter regions of mouse M and S opsin genes, but regulates their expression differentially, suppressing S opsin expression and, through interaction with the transcription factors CRX and TR2, enhancing M opsin expression. Null mutation of Gtf2ird1 leads to altered topology of cone opsin expression in the retina, with aberrant S opsin over-expression and M opsin under-expression in M cones. Gtf2ird1 null mice also demonstrate abnormal M cone electrophysiological responses. These findings indicate a dual and specific regulatory role of GTF2IRD1 in maintaining normal M cone-specific gene expression and function.

2014-12-31 | GSE54164 | GEO

Quantitative Analysis of transcriptome in Gad2+ neurons isolated from Wild Type and GTF2ird1-/-

Project description:The goals of this study are to compare transcriptome of Gad2 + inhibitory neurons, isolated from cerebral cortex of wild type and GTF2ird1-/- mice Wild type or GTF2ird1-/- were crossed with Gad2-Cre/Ai14, and total RNA was isolated from flow cytometry-sorted TdTomato positive cells

2022-09-23 | GSE195491 | GEO

Expression data from inducible ES stable cell line overexpressing specifically the human gene GTF2IRD1

Project description:In order to identify the effects of the induction of the gene of interest (GTF2IRD1) on the mouse ES transcriptome, we performed Affymetrix Gene-Chip hybridization experiments for the inducible not-tagged cell line Transcriptome analysis of the inducible transgenic mouse ES cell line overexpressing the human isorofm of the gene GTF2IRD1.

2019-10-11 | GSE95267 | GEO

Global gene expression in P0 Gtf2ird1-/- mouse brains

Project description:A compairson of gene expression in the brains of P0 Gtf2ird1-/- and wildtype mice using the GeneChip Mouse Genome 430 2.0 Array (Affymetrix)

2011-12-31 | E-MTAB-622 | biostudies-arrayexpress

Global gene expression in E15.5 Gtf2ird1-/- mouse emybro heads

Project description:A compairson of gene expression in the heads of E15.5 Gtf2ird1-/- and wildtype mouse embryos using the the Illumina Mouse WG-6 v2.0 Expression BeadChip

2011-12-31 | E-MTAB-626 | biostudies-arrayexpress

The role of GTF2IRD1 in the auditory pathology of Williams-Beuren Syndrome.

Project description:Williams-Beuren Syndrome (WBS) is a rare genetic condition caused by a hemizygous deletion involving up to 28 genes within chromosome 7q11.23. Among the spectrum of physical and neurological defects in WBS, it is common to find a distinctive response to sound stimuli that includes extreme adverse reactions to loud, or sudden sounds and a fascination with certain sounds that may manifest as strengths in musical ability. However, hearing tests indicate that sensorineural hearing loss (SNHL) is frequently found in WBS patients. The functional and genetic basis of this unusual auditory phenotype is currently unknown. Here, we investigated the potential involvement of GTF2IRD1, a transcription factor encoded by a gene located within the WBS deletion that has been implicated as a contributor to the WBS assorted neurocognitive profile and craniofacial abnormalities. Using Gtf2ird1 knockout mice, we have analysed the expression of the gene in the inner ear and examined hearing capacity by evaluating the auditory brainstem response (ABR) and the distortion product of otoacoustic emissions (DPOAE). Our results show that Gtf2ird1 is expressed in a number of cell types within the cochlea, and Gtf2ird1 null mice showed higher auditory thresholds (hypoacusis) in both ABR and DPOAE hearing assessments. These data indicate that the principal hearing deficit in the mice can be traced to impairments in the amplification process mediated by the outer hair cells and suggests that similar mechanisms may underpin the SNHL experienced by WBS patients.

| S-EPMC4795059 | biostudies-other

Negative autoregulation of GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding mechanism.

Project description:The GTF2IRD1 gene is of principal interest to the study of Williams-Beuren syndrome (WBS). This neurodevelopmental disorder results from the hemizygous deletion of a region of chromosome 7q11.23 containing 28 genes including GTF2IRD1. WBS is thought to be caused by haploinsufficiency of certain dosage-sensitive genes within the deleted region, and the feature of supravalvular aortic stenosis (SVAS) has been attributed to reduced elastin caused by deletion of ELN. Human genetic mapping data have implicated two related genes GTF2IRD1 and GTF2I in the cause of some the key features of WBS, including craniofacial dysmorphology, hypersociability, and visuospatial deficits. Mice with mutations of the Gtf2ird1 allele show evidence of craniofacial abnormalities and behavioral changes. Here we show the existence of a negative autoregulatory mechanism that controls the level of GTF2IRD1 transcription via direct binding of the GTF2IRD1 protein to a highly conserved region of the GTF2IRD1 promoter containing an array of three binding sites. The affinity for this protein-DNA interaction is critically dependent upon multiple interactions between separate domains of the protein and at least two of the DNA binding sites. This autoregulatory mechanism leads to dosage compensation of GTF2IRD1 transcription in WBS patients. The GTF2IRD1 promoter represents the first established in vivo gene target of the GTF2IRD1 protein, and we use it to model its DNA interaction capabilities.

| S-EPMC2836076 | biostudies-literature

Human MCF7 cells engineered to overexpress MYF6 vs. Control cells containing empty vector constructs [Rec1]

Project description:Background: Proliferation is an important hallmark of cancer development and progression. Tumor growth rate significantly influences the course of the disease, and patients with tumors that have a high proliferation rate have an increased risk (10-20%) of metastasis and death. The genomic region encoding the transcription factor MYF6 is often altered in breast cancer, and alterations in MYF6 methylation have been linked to several different cancer types. However, the functional role of MYF6 in cancer remain unknown. Here, we have dissected the functional role of MYF6 in ER+ breast cancer. Methods: We analyzed cancer cell growth, proliferation, apoptosis, in vivo tumor formation, EMT phenotype and BCSC propagation in MCF7 and T47D ER+ breast cancer models with inducuble MYF6 overexpression or MYF6 knockdown. Additionally, we performed detailed molecular profiling and network analysis, and Western blot validation of identified targets. Results: We show that MYF6 suppresses PI3K/Akt/mTOR and Wnt pathway signaling, two important pathways of cell proliferation, and suppression was accompanied by reduced cell growth in vitro and in vivo, and G0/G1 phase cell cycle arrest. MYF6 also induced an EMT phenotype and forced the cells into a cancer stem cell-like state, leading to resistance to -irradiation. Network analysis of molecular profiling data revealed that MYF6 activates hypoxia signaling and HIF1A was identified as a downstream target and an upstream regulator of MYF6. Conclusion: Our results suggest both a tumor-suppressive and oncogenic role of MYF6 in ER+ breast cancer, and we theorize that, subject to the presence or absence of yet unidentified cellular factors, MYF6 can switch from a growth-inhibiting tumor suppressor to an oncogene state, associated with cancer stem cells and treatment resistance.

2023-01-31 | GSE188505 | GEO

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