Chromosome conformation capture-on-chip analysis of long-range cis interactions of the SOX9 promoter
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE50449 | GEO | 2013/09/08
SECONDARY ACCESSION(S): PRJNA217510
REPOSITORIES: GEO
Similar Datasets
Project description:Transcription factor SOX9 is essential for the differentiation of chondrocytes and the development of testes. Heterozygous point mutations and genomic deletions involving SOX9 lead to campomelic dysplasia (CD) often associated with sex reversal. Chromosomal rearrangements with breakpoints mapping up to 1.3 Mb up- and downstream to SOX9, and likely disrupting its distant cis-regulatory elements, have been described in patients with milder forms of CD. Performing chromosome conformation capture-on-chip (4C) analysis in Sertoli cells and lymphoblasts we identified several novel potentially cis-interacting regions both up- and downstream to SOX9, with some of them overlapping lncRNA genes preferentially expressed in testes. Custom designed 3x720K tiling microarrays covering 4 Mb region (chr17:68,117,161-72,122,560) flanking SOX9 gene of interest
2013-09-08 | E-GEOD-50449 | biostudies-arrayexpress
Project description:The transcription factor Sox9 (Sry-Related HMG-Box gene 9) is essential in chondrogenesis. The expression Sox9 is regulated by 1.5Mb long range genomic region in temporospatial manner and genome translocation or deletion which affect Sox9 expression cause campomelic dysplasia (CD), characterized by skeletal malformations. Although functional mechanism of Sox9 are well studied so far, regulatory mechanism of Sox9 expression and its related enhancer in chondrocytes are largely remains to be elucidated. The purpose of this study is to identify Sox9 enhancers in chondrocytes
2024-06-10 | GSE237887 | GEO
Project description:The transcription factor Sox9 (Sry-Related HMG-Box gene 9) is essential in chondrogenesis. The expression Sox9 is regulated by 1.5Mb long range genomic region in temporospatial manner and genome translocation or deletion which affect Sox9 expression cause campomelic dysplasia (CD), characterized by skeletal malformations. Although functional mechanism of Sox9 are well studied so far, regulatory mechanism of Sox9 expression and its related enhancer in chondrocytes are largely remains to be elucidated. The purpose of this study is to identify Sox9 enhancers in chondrocytes
2024-06-10 | GSE237886 | GEO
Project description:The transcription factor Sox9 (Sry-Related HMG-Box gene 9) is essential in chondrogenesis. The expression Sox9 is regulated by 1.5Mb long range genomic region in temporospatial manner and genome translocation or deletion which affect Sox9 expression cause campomelic dysplasia (CD), characterized by skeletal malformations. Although functional mechanism of Sox9 are well studied so far, regulatory mechanism of Sox9 expression and its related enhancer in chondrocytes are largely remains to be elucidated. The purpose of this study is to identify Sox9 enhancers in chondrocytes
2024-06-10 | GSE237882 | GEO
Project description:Purpose: SOX9Y440X is the most commonly reported SOX9 mutation identified in human patients with Campomelic dysplasia, a dominant semi-lethal skeletal disease characterized by congenital shortening and angulation of long bones (campomelia). To understand how the SOX9Y440X mutant cause the abnormal limb development and compare with previously heterozygous Sox9 null mutant, a mouse model with Sox9Y440X mutation has been generated. The goal of this study is to carry out transcriptome analyses (RNA-seq) of E13.5 limbs collected from Sox9+/IRES-EGFP and Sox9+/Y440X-IRES-EGFP mice. GFP+ and GFP- cells were collected from each genotype by FACS. Comparing transcriptome profiles of cells from these two genotypes aims to reveal how the SOX9Y440X mutant causes abnormal limb development. Method: Forelimbs (FL) and hindlimbs (HL) mRNA profiles of E13.5 Sox9+/IRES-EGFP (WT) and Sox9+/Y440X-IRES-EGFP (CD) mice were generated by sequencing. 4-6 pairs of FL and HL buds were collected separately for each genotype. Limb tissues were then digested into single cells, then EGFP positive and negative cells were collected by FACS for each sample. Total RNA from each sample was prepared using Ambion RNA isolation kit (Cat. AM1580). 100ng of total RNA was used from each sample for RNA-sequencing. cDNA libraries were prepared by TruSeq Stranded mRNA Sample Prep Kit (Illumina). Pair-End sequencing of 101bp was done using HiSeq 1500 Sequencer Model. Data processing: Reads was pre-processed and aligned to the mouse GRCm38 (mm10) reference genome and expression levels were quantified using the nfcore/rnaseq workflow. The count matrix from featureCounts was used in the downstream analyses. The Nextflow pipeline for downstream analysis is available at https://github.com/fuxialexander/sox9. With R library edgeR 3.36.0, read counts were normalized using the ‘TMM’ method. We identified differentially expressed genes between the WT and CD groups in GFP+ or GFP- samples with the ‘glmQLFTest’ function and a Benjamini & Hochberg adjusted P-value cutoff of 0.05. Conclusions: Our study represents the first detailed analysis of mouse foetal limbs transcriptomes between Sox9Y440X mutant and wild type. Our work contributes to gain insight into the molecular signalling pathways affected by SOX9Y440X in vivo.
2022-12-31 | GSE201261 | GEO
Project description:Sensorineural deafness can occur in campomelic dysplasia (CD). In a mouse model of the SOX9Y440X/+ CD mutation, SOX10 downregulation was previously shown to be associated with impaired development of the endolymphatic system at mid-gestation. The underlying molecular causes are unknown. Here we found at E10.5 when the otocyst lacks overt inner ear structures, Sox10 was downregulated in the dorsal and medial aspects of the Sox9Y440X/+ otic epithelium, regions associated with specification of the endolymphatic sac and duct. Single-cell transcriptomic profiling revealed differential elevation of Wnt signaling pathway genes associated with the domain-specific Sox10 reduction. Otocyst-specific forced elevation of Wnt signaling by expression of stabilized β-catenin suppressed Sox10 expression. Similarly, WNT exerted an inhibitory effect on SOX10 expression in human inner ear organoids derived from pluripotent stem cells. We propose a conserved regulatory model of SOX9-WNT antagonism governing SOX10 action in the otocyst underlies the specification of endolymphatic cell fate, with important implications for understanding human deafness syndromes.
2024-11-07 | GSE271849 | GEO
Project description:The embryonic endolymphatic sac mediates fluid resorption for which anion exchangers such as SLC26A4, and its transcriptional activator FOXI1, are required. Apart from FOXI1, little is known about transcriptional regulators of this fluid balance. Altered fluid homeostasis in the inner ear is the leading cause of congenital hearing loss. Some patients with campomelic dysplasia (CD) caused by heterozygous mutations in SOX9, in addition to skeletal malformation, are deaf, with an unknown etiology. In a mouse model of CD caused by the SOX9Y440X mutation, which results in a truncated protein lacking the transactivation domain, we show severe endolymphatic dysfunction leading to deafness and vestibular problems. Adult heterozygous Sox9Y440X mice that express the mutation in the developing inner ear display sensorineural deafness combined with endolymphatic hydrops and lack of endocochlear potential. The mutant inner ear is enlarged from E15 and fewer Slc26a4-expressing cells are present in the endolymphatic epithelium. By single cell RNA sequencing of mutant and wild-type endolymphatic sacs we find marked reduction in genes important for ion transport such as Slc24a4 and Ttyh1 and gap-junctions such as Gjb2 and up-regulation of Wnt signaling and Igfbp2 that promotes progenitor proliferation. The cochlea overexpresses Aqp3, which encodes a water channel. We find by biochemical and cell-based transactivation assays and genetic interaction tests that SOX9 and SOX10 normally work co-operatively to repress Aqp3 transcription: SOX9Y440X blocks this repression by dominant interference. Our study reveals the key roles of SOXE transcription factors in the development of endolymphatic sac function, and highlight a molecular mechanism whereby the CD mutation exerts both a dominant negative and haploinsufficient mechanisms in different compartments of the inner ear to maintain fluid homeostasis. In the cochlea, SOX9 and SOX10 together repress aquaporin expression whereas in the endolymphatic sac, SOX9 controls SOX10 expression and genes for ion transport and gap-junctions. We postulate that in addition to loss of control of cell proliferation results in the exhaustion of progenitors which in turn leads to a deficit in mitochondria-rich cells. These results highlight a multifaceted mechanism for maintaining the proper fluid balance for hearing.
2022-10-10 | GSE131196 | GEO
Project description:The embryonic endolymphatic sac mediates fluid resorption for which anion exchangers such as SLC26A4, and its transcriptional activator FOXI1, are required. Apart from FOXI1, little is known about transcriptional regulators of this fluid balance. Altered fluid homeostasis in the inner ear is the leading cause of congenital hearing loss. Some patients with campomelic dysplasia (CD) caused by heterozygous mutations in SOX9, in addition to skeletal malformation, are deaf, with an unknown etiology. In a mouse model of CD caused by the SOX9Y440X mutation, which results in a truncated protein lacking the transactivation domain, we show severe endolymphatic dysfunction leading to deafness and vestibular problems. Adult heterozygous Sox9Y440X mice that express the mutation in the developing inner ear display sensorineural deafness combined with endolymphatic hydrops and lack of endocochlear potential. The mutant inner ear is enlarged from E15 and fewer Slc26a4-expressing cells are present in the endolymphatic epithelium. By single cell RNA sequencing of mutant and wild-type endolymphatic sacs we find marked reduction in genes important for ion transport such as Slc24a4 and Ttyh1 and gap-junctions such as Gjb2 and up-regulation of Wnt signaling and Igfbp2 that promotes progenitor proliferation. The cochlea overexpresses Aqp3, which encodes a water channel. We find by biochemical and cell-based transactivation assays and genetic interaction tests that SOX9 and SOX10 normally work co-operatively to repress Aqp3 transcription: SOX9Y440X blocks this repression by dominant interference. Our study reveals the key roles of SOXE transcription factors in the development of endolymphatic sac function, and highlight a molecular mechanism whereby the CD mutation exerts both a dominant negative and haploinsufficient mechanisms in different compartments of the inner ear to maintain fluid homeostasis. In the cochlea, SOX9 and SOX10 together repress aquaporin expression whereas in the endolymphatic sac, SOX9 controls SOX10 expression and genes for ion transport and gap-junctions. We postulate that in addition to loss of control of cell proliferation results in the exhaustion of progenitors which in turn leads to a deficit in mitochondria-rich cells. These results highlight a multifaceted mechanism for maintaining the proper fluid balance for hearing.
2022-10-10 | GSE139587 | GEO
Project description:We used two Sertoli-cell-specific Cre lines: Wt1-CreERT2 and Sox9-CreERT2, to induce Sox9 ablation on a Sox8 -/- background in the adult testis. Sox9/8 double KO testes undergo testis-to-ovary genetic reprogramming and Sertoli-to-granulosa cell transdifferentiation.
2016-06-08 | E-MTAB-4572 | biostudies-arrayexpress
Project description:In mammals, male fate is under the control of the master transcriptional regulator, SOX9: in its presence, somatic precursor cells of the embryonic gonads differentiate into Sertoli cells, the main organizers of testicular differentiation. Therefore, analyzing target genes of this transcription factor allows understanding mechanisms of cellular commitment at the genomic level. With the use of ChIP-seq in murine and bovine wild-type testes combined with RNAseq from mouse testes lacking SOX9, we identified SOX9 target genes in the mammalian fetal gonad. SOX9 in murine and bovine fetal testes binds to a large set of genes conserved among mammals, including those with well-established roles in testis and ovary development. RNAseq analysis shows that testis and ovary display sex specific RNA splicing and that SOX9 mediates both target gene transcription and differential splicing. Regions bound by SOX9 are predominantly 5’ proximal or intra-genic, and display a specific genomic features that we call "Sertoli cell signatures" or SCS. The SCS is conserved among mammals and comprises multiple binding motifs for the Sertoli reprogramming factors SOX9, GATA4 and DMRT1; indeed, independent DMRT1 ChIP-seq confirms the enrichment of the SCS. Bioinformatic analysis of SCSs regions predicts novel regulatory mechanisms prompting functional validation. For example, we detected SCS in target genes of the nuclear factor TRIM28 and we show experimentally that SOX9 and TRIM28 proteins interact in fetal testis.
2016-12-15 | GSE81488 | GEO