Direct targets of the transcription factor Six1 identify novel candidate deafness genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1169783 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30902646_1.fastq.gz | Fastqsanger.gz | |||
| SRR30902646_2.fastq.gz | Fastqsanger.gz | |||
| SRR30902647_1.fastq.gz | Fastqsanger.gz | |||
| SRR30902647_2.fastq.gz | Fastqsanger.gz | |||
| SRR30902648_1.fastq.gz | Fastqsanger.gz |
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Project description:Branchio-otic (BOS) and Branchio-oto-renal (BOR) syndromes are autosomal dominant disorders featuring multiple birth defects including ear, renal and branchial malformations. Mutations in the homeodomain transcription factor SIX1 and its co-factor EYA1 have been identified in about 50% of BOS/BOR patients, while causative mutations are unknown in the other half. We hypothesise that SIX1 target genes represent new BOS/BOR candidates. Using published transcriptomic and epigenomic data from chick ear progenitors, we first identify putative Six1 targets. Next, we provide evidence that Six1 directly regulates these targets: Six1 binds to their enhancers and functional experiments in Xenopus and chick confirm that Six1 controls their expression. Finally, we show that most chick Six1 targets are also expressed in the human developing ear and are associated with known deafness loci. Together, our results not only characterise the molecular mechanisms that mediate Six1 function in the developing ear, but also provide new candidates for human congenital deafness.
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Project description:Six1 is a developmental transcriptional regulator frequently overexpressed in human tumors. Recent results also show that SIX1 acts as a repressor of cell senescence, an antiproliferative response with key roles in tumor suppression, among other physiological and pathological settings. Here, we set to study the impact of SIX1 gain of function in transformation and tumorigenesis of fibroblasts, in connection with senescence. Using transcriptomic, histological, and functional analyses in murine cells and tumors of fibroblast origin, we show that SIX1 has a strong pro-tumorigenic action in this model, linked to the repression of a senescence-related gene signature and the activation of cellular plasticity, mediated at least in part by direct transcriptional regulation of the stemness factor Sox2. Moreover, functional analyses with human glioma cell lines also show that SIX1 controls SOX2 expression, senescence and self-renewal in this model. Collectively, our results support a general link of SIX1 with senescence and SOX2-mediated cell plasticity in tumors.
2019-02-12 | GSE113385 | GEO
Project description:Regulation of mRNA stability is a critical step in the control of gene expression. The nonsense mediated mRNA decay (NMD) pathway is one important mRNA stability pathway and has been shown to function in regulating a significant portion of the transcriptome. Perhaps the most significant outstanding question surrounding NMD regulation of endogenous gene expression is the identification of transcripts directly targeted by the NMD pathway versus secondary response genes, whose expression levels are dependent on the activity of direct targets. Here, we present for the first time in an intact animal, the experimental identification of direct targets of NMD. We find that most genes (74%) that are upregulated in NMD mutants appear not to be direct targets of NMD. More surprisingly, we find that the vast majority (97%) of candidate direct targets are not found to be increased in expression in a NMD mutant background. These results imply negative feedback renormalizes the levels of most direct targets of NMD, suggesting they would have been missed in previous analyses. We find that our candidate direct target genes have disproportionately long 3’ UTRs compared to non-targeted control genes. Long 3’ UTRs have been shown to target mRNAs for NMD in experimental systems, and our results imply this is the case in vivo. Our results will allow for the understanding of the function of the NMD pathway in endogenous gene regulation, during normal development, as well as in pathological states.
2013-07-01 | GSE47979 | GEO
Project description:Craniofacial development requires intricate cooperation of multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the function of Six1 in mandible development using a Six1 knockout mouse model (Six1-/-) and a cranial neural crest-specific, Six1 conditional knockout mouse model (Six1f/f; Wnt1-Cre). The Six1-/- mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Importantly, the Six1f/f; Wnt1-Cre mice recapitulate the microsomia phenotype of Six1-/- mice, thus demonstrating that the expression of Six1 in ectomesenchyme is critical for mandible development. We further showed that the knockout of Six1 led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of Six1 in C3H10 T1/2 cells reduced their osteogenic capacity in vitro. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and the Six1 knockdown in C3H10 T1/2 led to the dysregulation of genes involved in embryonal skeletal development. In particular, we showed that Six1 binds to the promoter of Bmp4, Fat4, Fgf18, and Fgfr2, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in the regulation of mandibular skeleton formation during mouse embryogenesis.
2023-03-10 | GSE216759 | GEO
Project description:Craniofacial development requires intricate cooperation of multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the function of Six1 in mandible development using a Six1 knockout mouse model (Six1-/-) and a cranial neural crest-specific, Six1 conditional knockout mouse model (Six1f/f; Wnt1-Cre). The Six1-/- mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Importantly, the Six1f/f; Wnt1-Cre mice recapitulate the microsomia phenotype of Six1-/- mice, thus demonstrating that the expression of Six1 in ectomesenchyme is critical for mandible development. We further showed that the knockout of Six1 led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of Six1 in C3H10 T1/2 cells reduced their osteogenic capacity in vitro. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and the Six1 knockdown in C3H10 T1/2 led to the dysregulation of genes involved in embryonal skeletal development. In particular, we showed that Six1 binds to the promoter of Bmp4, Fat4, Fgf18, and Fgfr2, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in the regulation of mandibular skeleton formation during mouse embryogenesis.
2023-03-10 | GSE216760 | GEO
Project description:Regulation of mRNA stability is a critical step in the control of gene expression. The nonsense mediated mRNA decay (NMD) pathway is one important mRNA stability pathway and has been shown to function in regulating a significant portion of the transcriptome. Perhaps the most significant outstanding question surrounding NMD regulation of endogenous gene expression is the identification of transcripts directly targeted by the NMD pathway versus secondary response genes, whose expression levels are dependent on the activity of direct targets. Here, we present for the first time in an intact animal, the experimental identification of direct targets of NMD. We find that most genes (74%) that are upregulated in NMD mutants appear not to be direct targets of NMD. More surprisingly, we find that the vast majority (97%) of candidate direct targets are not found to be increased in expression in a NMD mutant background. These results imply negative feedback renormalizes the levels of most direct targets of NMD, suggesting they would have been missed in previous analyses. We find that our candidate direct target genes have disproportionately long 3’ UTRs compared to non-targeted control genes. Long 3’ UTRs have been shown to target mRNAs for NMD in experimental systems, and our results imply this is the case in vivo. Our results will allow for the understanding of the function of the NMD pathway in endogenous gene regulation, during normal development, as well as in pathological states. Starting with a Nonsense Mediated Decay(NMD) mutant, in which expression levels of both primary and secondary NMD targets should be increased, we introduce a wild-type copy of the mutated factor and evaluated the transcriptome profile change overtime. Following reintroduction, expression levels of transcripts that are direct targets of NMD should decrease rapidly. Conversely, the levels of indirect targets will remain high until direct targets return to wild-type levels, which will occur later in the timecourse. This allows us to identify direct NMD targets.
2013-07-01 | E-GEOD-47979 | biostudies-arrayexpress
Project description:The overexpression of Six1, a member of the Six family of homeodomain transcription factors, has been found in various human cancers, and is associated with tumor progression and metastasis. We previously determined that the expression of Six1 mRNA increased during in vitro progression of human papillomavirus type 16 (HPV16)-immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. However, if Six1 promotes HPV16-mediated transformation or not remains unknown. HKc/DR were transfected with a Six1 or control vector and RNA isolated from these cells were used in an Agilent two-color gene expression profiling experiment. The goal was to determine the effects of Six1 on global gene expression. Two-condition experiment, Six1 vs. Control HKc/DR cells. Biological replicates: 4 Six1-transfected replicates and 4 control-transfected replicates.
2013-12-24 | E-GEOD-53589 | biostudies-arrayexpress