CHD7 binds to insulators during neuronal differentiation [CUT&Tag]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1244028 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32915100_1.fastq.gz | Fastqsanger.gz | |||
| SRR32915100_2.fastq.gz | Fastqsanger.gz | |||
| SRR32915101_1.fastq.gz | Fastqsanger.gz | |||
| SRR32915101_2.fastq.gz | Fastqsanger.gz | |||
| SRR32915102_1.fastq.gz | Fastqsanger.gz |
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Project description:Spiral ganglion neurons (SGNs) are crucial for hearing, and the loss of SGNs causes hearing loss. Stem cell-based therapies offer a promising approach for SGN regeneration and require understanding the mechanisms governing SGN differentiation. We investigated the chromatin remodeler CHD7 in SGN differentiation using immortalized multipotent otic progenitor (iMOP) cells. We demonstrate that CHD7 knockdown significantly impairs neuronal differentiation. Genome-wide analysis reveals CHD7 enrichment at diverse cis-regulatory elements, with notable enrichment at sites marked by the insulator-binding protein CTCF between topologically associating domains (TADs). Insulators marked by the enrichment of CHD7 and CTCF resided near genes critical for neuronal differentiation, including Mir9-2. Targeting these regulatory regions in iMOPs with CRISPR interference (CRISPRi) and activation (CRISPRa) increased miR9 transcription, irrespective of the method. The occlusion of the regulatory elements suggested that the insulators function to regulate gene expression. The study highlights CHD7 activity at insulators and underscores its importance in promoting neuronal differentiation.
2025-04-07 | GSE293323 | GEO
Project description:Spiral ganglion neurons (SGNs) are crucial for hearing, and the loss of SGNs causes hearing loss. Stem cell-based therapies offer a promising approach for SGN regeneration and require understanding the mechanisms governing SGN differentiation. We investigated the chromatin remodeler CHD7 in SGN differentiation using immortalized multipotent otic progenitor (iMOP) cells. We demonstrate that CHD7 knockdown significantly impairs neuronal differentiation. Genome-wide analysis reveals CHD7 enrichment at diverse cis-regulatory elements, with notable enrichment at sites marked by the insulator-binding protein CTCF between topologically associating domains (TADs). Insulators marked by the enrichment of CHD7 and CTCF resided near genes critical for neuronal differentiation, including Mir9-2. Targeting these regulatory regions in iMOPs with CRISPR interference (CRISPRi) and activation (CRISPRa) increased miR9 transcription, irrespective of the method. The occlusion of the regulatory elements suggested that the insulators function to regulate gene expression. The study highlights CHD7 activity at insulators and underscores its importance in promoting neuronal differentiation.
2025-04-07 | GSE293324 | GEO
Project description:CHD7 binds to insulators during neuronal differentiation [RNA-Seq]
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Project description:The chromodomain helicase DNA binding protein 7 (CHD7) is a nucleosome repositioner implicated in multiple cellular processes, including neuronal differentiation. We identified CHD7 marked sites at TAD boundaries that regulate neuronal differentiation in an otic stem cell line. We showed that CHD7 co-occupied CTCF sites genome-wide. We identified CTCF+ CHD7+ sites near an essential transcription factor, Sox11, required for otic neuronal differentiation. The Sox11 promoter and 3’ untranslated region (UTR) showed CHD7 enrichment. The CHD7-marked sites at the 3’UTR displayed histone marks corresponding to active transcription that resulted in Sox11 antisense transcripts. Blocking the singular CHD7-marked site with CRISPRi decreased neurite lengths, reduced neuronal marker expression (TUBB3), and attenuated Sox11 antisense transcripts. Sox11 antisense transcripts were previously suggested to form double-stranded RNA and degrade the Sox11 transcript. Surprisingly, the level of the Sox11 sense transcripts remained unaffected after CRISPRi. We propose that CHD7 at TAD boundaries modulate the chromatin accessibility of CTCF-marked insulators, altering the 3D chromatin organization and ultimately affecting gene expression. Our results implicate a general mechanism of CHD7 in facilitating neuronal differentiation and provide insight into CHD7 dysfunction in CHARGE syndrome, an intellectual developmental disability disorder.
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Project description:CHD7 marks TAD boundaries during neuronal differentiation [Cut & Tag]
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Project description:The chromodomain helicase DNA binding protein 7 (CHD7) is a nucleosome repositioner implicated in multiple cellular processes, including neuronal differentiation. We identified CHD7 marked sites at TAD boundaries that regulate neuronal differentiation in an otic stem cell line. We showed that CHD7 co-occupied CTCF sites genome-wide. We identified CTCF+ CHD7+ sites near an essential transcription factor, Sox11, required for otic neuronal differentiation. The Sox11 promoter and 3’ untranslated region (UTR) showed CHD7 enrichment. The CHD7-marked sites at the 3’UTR displayed histone marks corresponding to active transcription that resulted in Sox11 antisense transcripts. Blocking the singular CHD7-marked site with CRISPRi decreased neurite lengths, reduced neuronal marker expression (TUBB3), and attenuated Sox11 antisense transcripts. Sox11 antisense transcripts were previously suggested to form double-stranded RNA and degrade the Sox11 transcript. Surprisingly, the level of the Sox11 sense transcripts remained unaffected after CRISPRi. We propose that CHD7 at TAD boundaries modulate the chromatin accessibility of CTCF-marked insulators, altering the 3D chromatin organization and ultimately affecting gene expression. Our results implicate a general mechanism of CHD7 in facilitating neuronal differentiation and provide insight into CHD7 dysfunction in CHARGE syndrome, an intellectual developmental disability disorder.
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Project description:The chromodomain helicase DNA binding protein 7 (CHD7) is a nucleosome repositioner implicated in multiple cellular processes, including neuronal differentiation. We identified CHD7 marked sites at TAD boundaries that regulate neuronal differentiation in an otic stem cell line. We showed that CHD7 co-occupied CTCF sites genome-wide. We identified CTCF+ CHD7+ sites near an essential transcription factor, Sox11, required for otic neuronal differentiation. The Sox11 promoter and 3’ untranslated region (UTR) showed CHD7 enrichment. The CHD7-marked sites at the 3’UTR displayed histone marks corresponding to active transcription that resulted in Sox11 antisense transcripts. Blocking the singular CHD7-marked site with CRISPRi decreased neurite lengths, reduced neuronal marker expression (TUBB3), and attenuated Sox11 antisense transcripts. Sox11 antisense transcripts were previously suggested to form double-stranded RNA and degrade the Sox11 transcript. Surprisingly, the level of the Sox11 sense transcripts remained unaffected after CRISPRi. We propose that CHD7 at TAD boundaries modulate the chromatin accessibility of CTCF-marked insulators, altering the 3D chromatin organization and ultimately affecting gene expression. Our results implicate a general mechanism of CHD7 in facilitating neuronal differentiation and provide insight into CHD7 dysfunction in CHARGE syndrome, an intellectual developmental disability disorder.
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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.
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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.
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