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Mapping binding sites of SIN3 isoforms across the Drosophila genome.

ABSTRACT: 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.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE72171 | GEO | 2016/01/09

SECONDARY ACCESSION(S): PRJNA293235

REPOSITORIES: GEO

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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.

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Mapping binding sites of SIN3 isoforms across the Drosophila genome.

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