A chromatin code for alternative splicing involving an association between CTCF and HP1α proteins
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE60094 | GEO | 2014/09/30
SECONDARY ACCESSION(S): PRJNA257460
REPOSITORIES: GEO
Similar Datasets
Project description:Alternative splicing is primarily controlled by the activity of splicing factors and by the elongation of the RNA polymerase II (RNAPII). Recent experiments have suggested a new complex network of splicing regulation involving chromatin, transcription and multiple protein factors. In particular, the CCCTC-binding factor (CTCF), the Argonaute protein AGO1, and members of heterochromatin protein 1 (HP1) family have been implicated in the regulation of splicing associated to chromatin and the elongation of RNAPII. These results raise the question of whether these proteins may associate at the chromatin level to modulate alternative splicing. RNA extraction from MCF-7 and MCF-10A cell lines. Splicing changes between these two cell lines were measured using a splice junction array (Affymetrix HJAY).
2015-05-04 | E-GEOD-38864 | biostudies-arrayexpress
Project description:Alternative splicing is primarily controlled by the activity of splicing factors and by the elongation of the RNA polymerase II (RNAPII). Recent experiments have suggested a new complex network of splicing regulation involving chromatin, transcription and multiple protein factors. In particular, the CCCTC-binding factor (CTCF), the Argonaute protein AGO1, and members of heterochromatin protein 1 (HP1) family have been implicated in the regulation of splicing associated to chromatin and the elongation of RNAPII. These results raise the question of whether these proteins may associate at the chromatin level to modulate alternative splicing.
2015-05-04 | GSE38864 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-09-30 | E-GEOD-60094 | biostudies-arrayexpress
Project description:A chromatin code for alternative splicing involving an association between CTCF and HP1α proteins
| PRJNA257460 | ENA
Project description:Multivalent interactions between effector proteins and histone post-translational modifications are an elementary mechanism of dynamic chromatin signalling. Here we elucidate the mechanism how heterochromatin protein 1α (HP1α), a multivalent effector, is efficiently recruited to the silent chromatin state (marked by trimethylated H3 at Lys9, H3K9me3) while remaining highly dynamic. Employing chemically defined nucleosome arrays together with single-molecule total internal reflection fluorescence microscopy (smTIRFM), we demonstrate that the HP1α residence time on chromatin depends on the density of H3K9me3, as dissociated factors can rapidly rebind at neighbouring sites. Moreover, by chemically controlling HP1α dimerization we find that effector multivalency prolongs chromatin retention and, importantly, accelerates the association rate. This effect results from increased avidity together with strengthened nonspecific chromatin interactions of dimeric HP1α. We propose that accelerated chromatin binding is a key feature of effector multivalency, allowing for fast and efficient competition for binding sites in the crowded nuclear compartment.
| S-EPMC4557296 | biostudies-literature
Project description:The mechanism underlying enhancer-blocking by insulators is unclear. We explored the activity of human beta-globin HS5, the orthologue of the CTCF-dependent chicken HS4 insulator. An extra copy of HS5 placed between the beta-globin locus control region (LCR) and downstream genes on a transgene fulfills the classic predictions for an enhancer-blocker. Ectopic HS5 does not perturb the LCR but blocks gene activation by interfering with RNA pol II, activator and coactivator recruitment, and epigenetic modification at the downstream beta-globin gene. Underlying these effects, ectopic HS5 disrupts chromatin loop formation between beta-globin and the LCR, and instead forms a new loop with endogenous HS5 that topologically isolates the LCR. Both enhancer-blocking and insulator-loop formation depend on an intact CTCF site in ectopic HS5 and are sensitive to knock-down of the CTCF protein by siRNA. Thus, intrinsic looping activity of CTCF sites can nullify LCR function.
| S-EPMC2629272 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE39746: Argonaute proteins couple chromatin silencing to alternative splicing (exon array) GSE39748: Argonaute proteins couple chromatin silencing to alternative splicing (RNA IP-Seq) Refer to individual Series
2012-08-22 | E-GEOD-39749 | biostudies-arrayexpress
Project description:CTCF plays key roles in gene regulation, chromatin insulation, imprinting, X chromosome inactivation and organizing the higher-order chromatin architecture of mammalian genomes. Previous studies have mainly focused on the roles of the canonical CTCF isoform. Here, we explore the functions of an alternatively spliced human CTCF isoform in which exons 3 and 4 are skipped, producing a shorter isoform (CTCF-s). Functionally, we find that CTCF-s competes with the genome binding of canonical CTCF and binds a similar DNA sequence. CTCF-s binding disrupts CTCF/cohesin binding, alters CTCF-mediated chromatin looping and promotes the activation of IFI6 that leads to apoptosis. This effect is caused by an abnormal long-range interaction at the IFI6 enhancer and promoter. Taken together, this study reveals a non-canonical function for CTCF-s that antagonizes the genomic binding of canonical CTCF and cohesin, and that modulates chromatin looping and causes apoptosis by stimulating IFI6 expression.
| S-EPMC6449404 | biostudies-literature
Project description:Alternative splicing significantly contributes to proteomic diversity and mis-regulation of splicing can cause diseases in human. Although both genomic and chromatin features have been shown to associate with splicing, the mechanisms by which various chromatin marks influence splicing is not clear for the most part. Moreover, it is not known whether the influence of specific genomic features on splicing is potentially modulated by the chromatin context. Here we report a deep neural network (DNN) model for predicting exon inclusion based on comprehensive genomic and chromatin features. Our analysis in three cell lines shows that, while both genomic and chromatin features can predict splicing to varying degrees, genomic features are the primary drivers of splicing, and the predictive power of chromatin features can largely be explained by their correlation with genomic features; chromatin features do not yield substantial independent contribution to splicing predictability. However, our model identified specific interactions between chromatin and genomic features suggesting that the effect of genomic elements may be modulated by chromatin context.
| S-EPMC5558438 | biostudies-literature
Project description:The branch point (BP) is one of the three obligatory signals required for pre-mRNA splicing. In mammals, the degeneracy of the motif combined with the lack of a large set of experimentally verified BPs complicates the task of modeling it in silico, and therefore of predicting the location of natural BPs. Consequently, BPs have been disregarded in a considerable fraction of the genome-wide studies on the regulation of splicing in mammals. We present a new computational approach for mammalian BP prediction. Using sequence conservation and positional bias we obtained a set of motifs with good agreement with U2 snRNA binding stability. Using a Support Vector Machine algorithm, we created a model complemented with polypyrimidine tract features, which considerably improves the prediction accuracy over previously published methods. Applying our algorithm to human introns, we show that BP position is highly dependent on the presence of AG dinucleotides in the 3' end of introns, with distance to the 3' splice site and BP strength strongly correlating with alternative splicing. Furthermore, experimental BP mapping for five exons preceded by long AG-dinucleotide exclusion zones revealed that, for a given intron, more than one BP can be chosen throughout the course of splicing. Finally, the comparison between exons of different evolutionary ages and pseudo exons suggests a key role of the BP in the pathway of exon creation in human. Our computational and experimental analyses suggest that BP recognition is more flexible than previously assumed, and it appears highly dependent on the presence of downstream polypyrimidine tracts. The reported association between BP features and the splicing outcome suggests that this, so far disregarded but yet crucial, element buries information that can complement current acceptor site models.
| S-EPMC2991248 | biostudies-literature