Mutually exclusive epigenetic modification on SIX6 with hypermethylation for precancerous stage and metastasis emergence tracing.
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ABSTRACT:
SUBMITTER: Dong S
PROVIDER: S-EPMC9256699 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAlterations in epigenetic marks, including methylation or acetylation, are common in human cancers. For many epigenetic pathways, however, direct measures of activity are unknown, making their role in various cancers difficult to assess. Gene expression signatures facilitate the examination of patterns of epigenetic pathway activation across and within human cancer types allowing better understanding of the relationships between these pathways.MethodsWe used Bayesian regression to generate gene expression signatures from normal epithelial cells before and after epigenetic pathway activation. Signatures were applied to datasets from TCGA, GEO, CaArray, ArrayExpress, and the cancer cell line encyclopedia. For TCGA data, signature results were correlated with copy number variation and DNA methylation changes. GSEA was used to identify biologic pathways related to the signatures.ResultsWe developed and validated signatures reflecting downstream effects of enhancer of zeste homolog 2(EZH2), histone deacetylase(HDAC) 1, HDAC4, sirtuin 1(SIRT1), and DNA methyltransferase 2(DNMT2). By applying these signatures to data from cancer cell lines and tumors in large public repositories, we identify those cancers that have the highest and lowest activation of each of these pathways. Highest EZH2 activation is seen in neuroblastoma, hepatocellular carcinoma, small cell lung cancer, and melanoma, while highest HDAC activity is seen in pharyngeal cancer, kidney cancer, and pancreatic cancer. Across all datasets studied, activation of both EZH2 and HDAC4 is significantly underrepresented. Using breast cancer and glioblastoma as examples to examine intrinsic subtypes of particular cancers, EZH2 activation was highest in luminal breast cancers and proneural glioblastomas, while HDAC4 activation was highest in basal breast cancer and mesenchymal glioblastoma. EZH2 and HDAC4 activation are associated with particular chromosome abnormalities: EZH2 activation with aberrations in genes from the TGF and phosphatidylinositol pathways and HDAC4 activation with aberrations in inflammatory and chemokine related genes.ConclusionGene expression patterns can reveal the activation level of epigenetic pathways. Epigenetic pathways define biologically relevant subsets of human cancers. EZH2 activation and HDAC4 activation correlate with growth factor signaling and inflammation, respectively, and represent two distinct states for cancer cells. This understanding may allow us to identify targetable drivers in these cancer subsets.
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Project description:Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi-cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila Finally, MXEs are significantly enriched in pathogenic mutations and their spatio-temporal expression might predict human disease pathology.
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Project description:Alternative splicing can expand the diversity of proteomes. Homologous mutually exclusive exons (MXEs) originate from the same ancestral exon and result in polypeptides with similar structural properties but altered sequence. Why would some genes switch homologous exons and what are their biological impact? Here, we analyse the extent of sequence, structural and functional variability in MXEs and report the first large scale, structure-based analysis of the biological impact of MXE events from different genomes. MXE-specific residues tend to map to single domains, are highly enriched in surface exposed residues and cluster at or near protein functional sites. Thus, MXE events are likely to maintain the protein fold, but alter specificity and selectivity of protein function. This comprehensive resource of MXE events and their annotations is available at: http://gene3d.biochem.ucl.ac.uk/mxemod/. These findings highlight how small, but significant changes at critical positions on a protein surface are exploited in evolution to alter function.
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Project description:The Down syndrome cell adhesion molecule (Dscam) gene has essential roles in neural wiring and pathogen recognition in Drosophila melanogaster. Dscam encodes 38,016 distinct isoforms via extensive alternative splicing. The 95 alternative exons in Dscam are organized into clusters that are spliced in a mutually exclusive manner. The exon 6 cluster contains 48 variable exons and uses a complex system of competing RNA structures to ensure that only one variable exon is included. Here we show that the heterogeneous nuclear ribonucleoprotein hrp36 acts specifically within, and throughout, the exon 6 cluster to prevent the inclusion of multiple exons. Moreover, hrp36 prevents serine/arginine-rich proteins from promoting the ectopic inclusion of multiple exon 6 variants. Thus, the fidelity of mutually exclusive splicing in the exon 6 cluster is governed by an intricate combination of alternative RNA structures and a globally acting splicing repressor.
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Project description:The cellular uptake of self-assembled biological and synthetic matter results from their multicomponent properties. However, the interplay of the building block composition of self-assembled materials and uptake mechanisms urgently requires addressing. It is shown here that supramolecular polymers that self-assemble in aqueous media, are a modular and controllable platform to modulate cellular delivery by the introduction of small ligands or cationic moieties, with concomitantly different cellular uptake kinetics and valence dependence. A library of supramolecular copolymers revealed stringent mutually exclusive uptake behavior in which either of the uptake pathways dominated, with sharp compositional transition. Supramolecular biomaterial engineering thus provides for adaptive platforms with great potential for efficient tuning of multivalent and multicomponent systems interfacing with biological matter.
| S-EPMC6282950 | biostudies-literature
Project description:BackgroundGenes of advanced organisms undergo alternative splicing, which can be mutually exclusive, in the sense that only one exon is included in the mature mRNA out of a cluster of alternative choices, often arranged in a tandem array. In many cases, however, the details of the underlying biologic mechanisms are unknown.ResultsWe describe 'variable window binding'--a mechanism used for mutually exclusive alternative splicing by which a segment ('window') of a conserved nucleotide 'anchor' sequence upstream of the exon 6 cluster in the pre-mRNA of the fruitfly Dscam gene binds to one of the introns, thereby activating selection of the exon directly downstream from the binding site. This mechanism is supported by the fact that the anchor sequence can be inferred solely from a comparison of the intron sequences using a genetic algorithm. Because the window location varies for each exon choice, regulation can be achieved by obstructing part of that sequence. We also describe a related mechanism based on competing pre-mRNA stem-loop structures that could explain the mutually exclusive choice of exon 17 of the Dscam gene.ConclusionOn the basis of comparative sequence analysis, we propose efficient biologic mechanisms of alternative splicing of the Drosophila Dscam gene that rely on the inherent structure of the pre-mRNA. Related mechanisms employing 'locus control regions' could be involved on other occasions of mutually exclusive choices of exons or genes.
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Project description:The nuclear cap-binding complex (CBC) stimulates processing reactions of capped RNAs, including their splicing, 3'-end formation, degradation, and transport. CBC effects are particular for individual RNA families, but how such selectivity is achieved remains elusive. Here, we analyze three main CBC partners known to impact different RNA species. ARS2 stimulates 3'-end formation/transcription termination of several transcript types, ZC3H18 stimulates degradation of a diverse set of RNAs, and PHAX functions in pre-small nuclear RNA/small nucleolar RNA (pre-snRNA/snoRNA) transport. Surprisingly, these proteins all bind capped RNAs without strong preferences for given transcripts, and their steady-state binding correlates poorly with their function. Despite this, PHAX and ZC3H18 compete for CBC binding and we demonstrate that this competitive binding is functionally relevant. We further show that CBC-containing complexes are short lived in vivo, and we therefore suggest that RNA fate involves the transient formation of mutually exclusive CBC complexes, which may only be consequential at particular checkpoints during RNA biogenesis.
2017-03-03 | GSE94427 | GEO
Project description:Domain swapping is a mechanism for forming protein dimers and oligomers with high specificity. It is distinct from other forms of oligomerization in that the binding interface is formed by reciprocal exchange of polypeptide segments. Swapping plays a physiological role in protein-protein recognition, and it can also potentially be exploited as a mechanism for controlled self-assembly. Here, we demonstrate that domain-swapped interfaces can be engineered by inserting one protein into a surface loop of another protein. The key to facilitating a domain swap is to destabilize the protein when it is monomeric but not when it is oligomeric. We achieve this condition by employing the "mutually exclusive folding" design to apply conformational stress to the monomeric state. Ubiquitin (Ub) is inserted into one of six surface loops of barnase (Bn). The 38-Å amino-to-carboxy-terminal distance of Ub stresses the Bn monomer, causing it to split at the point of insertion. The 2.2-Å X-ray structure of one insertion variant reveals that strain is relieved by intermolecular folding with an identically unfolded Bn domain, resulting in a domain-swapped polymer. All six constructs oligomerize, suggesting that inserting Ub into each surface loop of Bn results in a similar domain-swapping event. Binding affinity can be tuned by varying the length of the peptide linkers used to join the two proteins, which modulates the extent of stress. Engineered, swapped proteins have the potential to be used to fabricate "smart" biomaterials, or as binding modules from which to assemble heterologous, multi-subunit protein complexes.
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Project description:Comprehensive protein interaction maps can complement genetic and biochemical experiments and allow the formulation of new hypotheses to be tested in the system of interest. The computational analysis of the maps may help to focus on interesting cases and thereby to appropriately prioritize the validation experiments. We show here that, by automatically comparing and analyzing structurally similar regions of proteins of known structure interacting with a common partner, it is possible to identify mutually exclusive interactions present in the maps with a sensitivity of 70% and a specificity higher than 85% and that, in about three fourth of the correctly identified complexes, we also correctly recognize at least one residue (five on average) belonging to the interaction interface. Given the present and continuously increasing number of proteins of known structure, the requirement of the knowledge of the structure of the interacting proteins does not substantially impact on the coverage of our strategy that can be estimated to be around 25%. We also introduce here the Estrella server that embodies this strategy, is designed for users interested in validating specific hypotheses about the functional role of a protein-protein interaction and it also allows access to pre-computed data for seven organisms.
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Project description:The nuclear cap-binding complex (CBC) stimulates processing reactions of capped RNAs, including their splicing, 3'-end formation, degradation, and transport. CBC effects are particular for individual RNA families, but how such selectivity is achieved remains elusive. Here, we analyze three main CBC partners known to impact different RNA species. ARS2 stimulates 3'-end formation/transcription termination of several transcript types, ZC3H18 stimulates degradation of a diverse set of RNAs, and PHAX functions in pre-small nuclear RNA/small nucleolar RNA (pre-snRNA/snoRNA) transport. Surprisingly, these proteins all bind capped RNAs without strong preferences for given transcripts, and their steady-state binding correlates poorly with their function. Despite this, PHAX and ZC3H18 compete for CBC binding and we demonstrate that this competitive binding is functionally relevant. We further show that CBC-containing complexes are short lived in vivo, and we therefore suggest that RNA fate involves the transient formation of mutually exclusive CBC complexes, which may only be consequential at particular checkpoints during RNA biogenesis.
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