Ontology highlight
ABSTRACT:
PROVIDER: PRJNA748013 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15192393.fastq.gz | Fastqsanger.gz | |||
| SRR15192393_1.fastq.gz | Fastqsanger.gz | |||
| SRR15192393_2.fastq.gz | Fastqsanger.gz |
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Project description:Chromoanagenesis event underlies a de novo pericentric and multiple paracentric inversions in a single chromosome causing Coffin-Siris Syndrome
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Project description:Chromoanagenesis is a descriptive term that encompasses classes of catastrophic mutagenic processes that generate localized and complex chromosome rearrangements in both somatic and germline genomes. Herein we describe a 5-year-old female presenting with a constellation of clinical features consistent with a clinical diagnosis of Coffin-Siris syndrome 1 (CSS1). Initial G-banded karyotyping detected a 90 Mb pericentric and 47 Mb paracentric inversion on a single chromosome. Subsequent analysis using short-read whole genome sequencing, and genomic optical mapping revealed additional inversions, all clustered on chromosome 6, one of them disrupting ARID1B for which haploinsufficiency leading to CSS1. In all, the resolved derivative chromosome architecture presents four de novo inversions, one pericentric and three paracentric, involving six breakpoint junctions in what appears to be a shuffling of genomic material on this chromosome. Each junction was resolved to nucleotide-level resolution with mutational signatures suggestive of non-homologous end joining. The disruption of the gene ARID1B is shown to occur between the 4th and 5th exon of the canonical transcript with subsequent qPCR studies confirming a decrease in ARID1B expression in the patient versus healthy controls. Deciphering the underlying genomic architecture of chromosomal rearrangements and complex structural variants may require multiple technologies and can be critical to elucidating the molecular etiology of a patient’s clinical phenotype or resolving unsolved Mendelian disease cases.
2021-07-22 | GSE180423 | GEO
Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.
2021-10-12 | PXD028557 | Pride
Project description:De-novo ARID1B haploinsufficient mutations cause many developmental disorders characterized by neurological and craniofacial phenotypes, including Coffin-Siris Syndrome. ARID1B and its paralog ARID1A encode for mutually exclusive subunits of the BAF chromatin remodeler, yet their role in cell-fate determination is poorly understood. We discovered a novel neural crest configuration of the BAF complex (ARID1B-BAF), which includes ARID1B, SMARCA4, and eight additional subunits. The ARID1B-BAF regulates lineage commitment upon differentiation cues through attenuation of pluripotency enhancers of the SOX2 network. Consistently, the ARID1B-BAF interacts with SALL4, which is known to have repressing abilities during lineage commitment. In iPSCs, pluripotency enhancers are maintained in active state by cooperation between the pioneer activity of SOX2 and the ARID1A-containing BAF. At the onset of differentiation, ARID1B-BAF replaces ARID1A-BAF at these enhancers, eliciting chromatin repression and coordinating the exit from pluripotency. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at the pluripotency enhancers throughout CNCC differentiation. This correlates with aberrant SOX2 binding at the pluripotency enhancers, and failure to reposition SOX2 at the developmental enhancers. SOX2 dysregulation promotes upregulation of the NANOG regulatory network, impairing CNCC differentiation. Intriguingly, the patient with the most extreme molecular phenotype is also affected by a more severe version of the syndrome. These findings have significant biomedical implications, since they suggest a direct connection between ARID1B mutations and developmental disorders.
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Project description:Position-effect variegation (PEV) is the stochastic transcriptional silencing of a gene positioned adjacent to heterochromatin. white-mottled X-chromosomal inversions in Drosophila are classic PEV models that show variegation of the eye color gene white due to its relocation next to pericentric heterochromatin. To obtain insight into the mechanism of PEV, we constructed detailed binding maps of Heterochromatin Protein 1 (HP1), a major component of heterochromatin, on white-mottled chromosomes. We find that HP1 invades euchromatin across the inversion breakpoints over ~175kb and ~30kb, causing de novo association of HP1 with 20 genes. However, HP1 binding levels in these regions show substantial local variation; white is most strongly bound by HP1 and is one of only two genes that are substantially repressed by heterochromatin. HP1 binding to the invaded region is exceptionally sensitive to the dosage of the histone methyltransferase Su(var)3-9, indicating that the de novo formed heterochromatin is relatively unstable. Our molecular maps demonstrate that heterochromatin can invade a normally euchromatic region, yet the strength of HP1 binding and effects on gene expression are highly dependent on local context. Keywords: DamID, gene expression, genetic modification.
2009-02-18 | GSE12395 | GEO
Project description:Unbalanced translocations are a relatively common type of copy number variation and are a major contributor to neurodevelopmental disorders. We analyzed the breakpoints of 57 unique unbalanced translocations to investigate the mechanisms of how they form. 51 are simple unbalanced translocations between two different chromosome ends, and six rearrangements have more than three breakpoints involving two to five chromosomes. Sequencing 37 breakpoint junctions revealed that simple translocations have between zero and four basepairs (bp) of microhomology (n=26), short inserted sequences (n=8), or paralogous repeats (n=3) at the junctions, indicating that translocations do not arise primarily from non-allelic homologous recombination, but instead form most often via non-homologous end joining or microhomology-mediated break-induced replication. Three simple translocations fuse genes that are predicted to produce in-frame transcripts of SIRPG-WWOX, SMOC2-PROX1, and PIEZO2-MTA1, which may lead to gain of function. Three complex translocations have inversions, insertions, and multiple breakpoint junctions between only two chromosomes. Whole- genome sequencing and fluorescence in situ hybridization analysis of two de novo translocations revealed at least 18 and 33 breakpoints involving five different chromosomes. Breakpoint sequencing of one inherited translocation involving four chromosomes uncovered multiple breakpoints with inversions and insertions. All of these breakpoint junctions had zero to four bp of microhomology consistent with germline chromothripsis, and both de novo events occurred on paternal alleles. Breakpoint sequencing of our large collection of chromosome rearrangements offers a comprehensive analysis of the molecular mechanisms behind germline translocation formation. High resolution array CGH; two-color experiment, clinical patient vs. normal control gDNA; sex mis-matched
2015-04-22 | E-GEOD-68019 | biostudies-arrayexpress
Project description:The centromere-specific Histone H3-variant CENH3 (also known as CENP-A) is considered to be an epigenetic mark for establishment and propagation of centromere identity. Pulse-induction of CENH3 (Drosophila CID) in Schneider S2 cells incorporates into noncentromeric regions and generates CID islands that resist clearing from chromosome arms for multiple cell generations. We demonstrate that CID islands represent functional ectopic kinetochores, which are non-randomly distributed on the chromosome and display a preferential localization near telomeres and pericentric heterochromatin in transcriptionally silent, intergenic chromatin domains. Although overexpression of heterochromatin protein 1 (HP1) or increasing Histone acetylation interferes with CID islands formation on a global scale, induction of a locally defined region of synthetic heterochromatin by targeting HP1-LacI fusions to stably integrated Lac Operator arrays produces a proximal hotspot for CID islands formation. These data suggest that the characteristics of regions bordering heterochromatin promote de novo kinetochore assembly and thereby contribute to centromere identity.
2011-07-15 | E-MTAB-652 | biostudies-arrayexpress
Project description:The cohesin complex has crucial roles in many structural and functional aspects of chromosomes including sister chromatid cohesion, genome organization, gene transcription and DNA repair. Cohesin recruitment onto chromosomes requires nucleosome free DNA and a specialized cohesin loader complex comprised of the Scc2 and Scc4 subunits. The cohesin loader, in addition to stimulating cohesin ATP hydrolysis and facilitating topological loading onto DNA, leads cohesin to chromatin receptors such as the RSC chromatin remodeling complex. Here, we explore the cohesin loader-RSC interaction and show that its Scc4 subunit contacts a conserved RSC ATPase motor module. The cohesin loader enhances RSC chromatin remodeling activity in vitro, as well as promoter nucleosome eviction in vivo. These findings provide insight into how the cohesin loader recognizes, as well as influences, the chromatin landscape, with implications for our understanding of human developmental disorders including Cornelia de Lange and Coffin-Siris syndromes.
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