Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism disorder
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA718461 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14102300.fastq.gz | Fastqsanger.gz | |||
| SRR14102301.fastq.gz | Fastqsanger.gz | |||
| SRR14102302.fastq.gz | Fastqsanger.gz | |||
| SRR14102303.fastq.gz | Fastqsanger.gz | |||
| SRR14102304.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 13 |
Similar Datasets
Project description:Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ~230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
2021-03-31 | GSE171119 | GEO
Project description:Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ∼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
| S-EPMC8206166 | biostudies-literature
Project description:Sin3A and Sin3B bind to distinct and overlapping target sites. Sin3 proteins bind to distinct sites in cycling myoblasts whereas there is a converge of Sin3A and Sin3B proteins to sites in differentiated myotubes. We identified a subset of Sin3 target genes involved in muscle differentiation and physiology and showed that conditional ablation of Sin3 proteins in vivo in mouse results in sarcomere defects Examination of Sin3A and Sin3B binding during myogenesis
2011-01-01 | E-GEOD-22554 | biostudies-arrayexpress
Project description:Sin3A and Sin3B bind to distinct and overlapping target sites. Sin3 proteins bind to distinct sites in cycling myoblasts whereas there is a converge of Sin3A and Sin3B proteins to sites in differentiated myotubes. We identified a subset of Sin3 target genes involved in muscle differentiation and physiology and showed that conditional ablation of Sin3 proteins in vivo in mouse results in sarcomere defects
2011-01-01 | GSE22554 | GEO
Project description:Illumina whole genome SNP (single nucleotide polymorphism) microarray analysis was carried out on the patient in order to determine copy number variations and to assess their disease etiopathogenesis.
2020-03-31 | GSE147730 | GEO
Project description:Recent work from others and us revealed interactions between the Sin3/HDAC complex, the H3K4me3 demethylase KDM5A, GATAD1 and EMSY. Here, we characterize the EMSY/KDM5A/SIN3B complex in detail by quantitative interaction proteomics and ChIP-sequencing. We identify a novel substoichiometric interactor of the complex, ZNF131, which recruits EMSY to a large number of active, H3K4me3 marked promoters. Interestingly, using an EMSY knock-out line and subsequent rescue experiments, we show that EMSY is in most cases positively correlated with transcriptional activity of its target genes and stimulates cell proliferation. Finally, by immunohistochemical staining of primary breast tissue microarrays we find that EMSY/KDM5A/SIN3B complex subunits are frequently overexpressed in primary breast cancer cases in a correlative manner. Taken together, these data open venues for exploring the possibility that sporadic breast cancer patients with EMSY amplification might benefit from epigenetic combination therapy targeting both the KDM5A demethylase and histone deacetylases.
2017-12-11 | GSE75566 | GEO
Project description:BackgroundLarge-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.MethodsWhole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members.ResultsWe identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss.ConclusionsWhile POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.
| S-EPMC4702300 | biostudies-literature
Project description:SIN3 associates with RPD3 and other accessory proteins to form the SIN3 histone modifying complex. A single Sin3A gene encodes multiple SIN3 isoforms, of which SIN3 187 and SIN3 220 are predominant. Previous studies from our laboratory and others have indicated that SIN3 isoforms play non-redundant roles during fly development, however, the genes regulated by SIN3 isoforms are not known. We mapped the genome-wide binding sites of SIN3 isoforms in Drosophila. We established stable S2 cell lines that express either HA-tagged SIN3 187 or SIN3 220. The binding profiles revealed that the majority of the binding sites of SIN3 isoforms are overlapping. Our data revealed that SIN3 isoforms localize to euchromatic regions of the genome and enrichment of SIN3 isoforms are generally concentrated around the transcription start sites of genes. In addition, the extent of SIN3 binding confirmed previous findings indicating that SIN3 is a global transcriptional regulator.
2016-01-09 | GSE72171 | GEO
Project description:SIN3 associates with RPD3 and other accessory proteins to form the SIN3 histone modifying complex. A single Sin3A gene encodes multiple SIN3 isoforms, of which SIN3 187 and SIN3 220 are predominant. Previous studies from our laboratory and others have indicated that SIN3 isoforms play non-redundant roles during fly development, however, the genes regulated by SIN3 isoforms are not known. We mapped the genome-wide binding sites of SIN3 isoforms in Drosophila. We established stable S2 cell lines that express either HA-tagged SIN3 187 or SIN3 220. The binding profiles revealed that the majority of the binding sites of SIN3 isoforms are overlapping. Our data revealed that SIN3 isoforms localize to euchromatic regions of the genome and enrichment of SIN3 isoforms are generally concentrated around the transcription start sites of genes. In addition, the extent of SIN3 binding confirmed previous findings indicating that SIN3 is a global transcriptional regulator. Genome-wide binding analysis of SIN3 187 and SIN3 220 in Drosophila. Using chromatin prepared from cell lines expressing either of the isoforms, we performed chromatin immunoprecipitation on chromatin prepared from cells that expresses either of the isoforms using an antibody against HA (ChIP). We coupled our ChIP with high resolution deep sequencing (ChIP-seq) to identify genomic targets of SIN3 isoforms.
2016-01-09 | E-GEOD-72171 | biostudies-arrayexpress
Project description:Human disease mutation discovery has so far been biased towards protein coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel re-sequencing of the non-repetitive genomic linkage interval of the MRX3 family at Xq28. We identified a regulatory mutation in the YY1 transcription factor binding site, which leads to overexpression of the chromatin-associated transcriptional regulator, HCFC1. When tested on embryonic murine neural stem cells (NSCs) and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and considerable reduction in neurite growth. Two other non-synonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function.
2012-09-01 | GSE39326 | GEO