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Epigenetic features are significantly associated with alternative splicing.

ABSTRACT: BACKGROUND: While alternative splicing (AS) contributes greatly to protein diversities, the relationship between various types of AS and epigenetic factors remains largely unknown. RESULTS: In this study, we discover that a number of epigenetic features, including DNA methylation, nucleosome occupancy, specific histone modifications and protein features, are strongly associated with AS. To further enhance our understanding of the association between these features and AS, we cluster our investigated features based on their association patterns with each AS type into four groups, with H3K36me3, EGR1, GABP, SRF, SIN3A and RNA Pol II grouped together and showing strongest association with AS. In addition, we find that the AS types can be classified into two general classes, namely the exon skipping related process (ESRP), and the alternative splice site selection process (ASSP), based on their association levels with the epigenetic features. CONCLUSION: Our analysis thus suggests that epigenetic features are likely to play important roles in regulating AS.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC3362759 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Epigenetic features are significantly associated with alternative splicing.

Zhou Yuanpeng Y Lu Yulan Y Tian Weidong W

BMC genomics 20120329

<h4>Background</h4>While alternative splicing (AS) contributes greatly to protein diversities, the relationship between various types of AS and epigenetic factors remains largely unknown.<h4>Results</h4>In this study, we discover that a number of epigenetic features, including DNA methylation, nucleosome occupancy, specific histone modifications and protein features, are strongly associated with AS. To further enhance our understanding of the association between these features and AS, we cluster ...[more]

PMID: 22455468

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Project description:BackgroundAlternative splicing events (ASEs) are vital causes of tumor heterogeneity in genitourinary tumors and many other cancers. However, the clinicopathological relevance of ASEs in cancers has not yet been comprehensively characterized.MethodsBy analyzing splicing data from the TCGA SpliceSeq database and phenotype data for all TCGA samples from the UCSC Xena database, we identified differential clinical feature-related ASEs in 33 tumors. CIBERSORT immune cell infiltration data from the TIMER2.0 database were used for differential clinical feature-related immune cell infiltration analysis. Gene function enrichment analysis was used to analyze the gene function of ASEs related to different clinical features in tumors. To reveal the regulatory mechanisms of ASEs, we integrated race-related ASEs and splicing quantitative trait loci (sQTLs) data in kidney renal clear cell carcinoma (KIRC) to comprehensively assess the impact of SNPs on ASEs. In addition, we predicted regulatory RNA binding proteins in bladder urothelial carcinoma (BLCA) based on the enrichment of motifs around alternative exons for ASEs.ResultsAlternative splicing differences were systematically analyzed between different groups of 58 clinical features in 33 cancers, and 30 clinical features in 24 cancer types were identified to be associated with more than 50 ASEs individually. The types of immune cell infiltration were found to be significantly different between subgroups of primary diagnosis and disease type. After integrating ASEs with sQTLs data, we found that 63 (58.9%) of the race-related ASEs were significantly SNP-correlated ASEs in KIRC. Gene function enrichment analyses showed that metastasis-related ASEs in KIRC mainly enriched Rho GTPase signaling pathways. Among those ASEs associated with metastasis, alternative splicing of GIT2 and TUBB3 might play key roles in tumor metastasis in KIRC patients. Finally, we identified several RNA binding proteins such as PCBP2, SNRNP70, and HuR, which might contribute to splicing differences between different groups of neoplasm grade in BLCA.ConclusionWe demonstrated the significant clinical relevance of ASEs in multiple cancer types. Furthermore, we identified and validated alternative splicing of TUBB3 and RNA binding proteins such as PCBP2 as critical regulators in the progression of urogenital cancers.

Project description:PurposeAlzheimer disease (AD) is one of the most complex diseases and is characterized by AD-related neuropathological features, including accumulation of amyloid-β plaques and tau neurofibrillary tangles. Dysregulation of alternative splicing (AS) contributes to these features, and there is heterogeneity in features across brain regions between AD patients, leading to different severity and progression rates; however, brain region-specific AS mechanisms still remain unclear. Therefore, we aimed to systemically investigate AS in multiple brain regions of AD patients and how they affect clinical features.MethodsWe analyzed RNA sequencing (RNA-Seq) data obtained from brain regions (frontal and temporal) of AD patients. Reads were mapped to the hg19 reference genome using the STAR aligner, and exon skipping (ES) rates were estimated as percent spliced in (PSI) by rMATs. We focused on AD-risk genes discovered by genome-wide association studies, and accordingly evaluated associations between PSI of skipped exons in AD-risk genes and Braak stage and plaque density mean (PM) for each brain region. We also integrated whole-genome sequencing data of the ascertained samples with RNA-Seq data to identify genetic regulators of feature-associated ES.ResultsWe identified 26 and 41 ES associated with Braak stage in frontal and temporal regions, respectively, and 10 and 50 ES associated with PM. Among those, 10 were frontal-specific (CLU and NTRK2), 65 temporal-specific (HIF1A and TRPC4AP), and 26 shared ES (APP) that accompanied functional Gene Ontology terms, including axonogenesis in shared-ES genes. We further identified genetic regulators that account for 44 ES (44% of the total). Finally, we present as a case study the systematic regulation of an ES in APP, which is important in AD pathogenesis.ConclusionThis study provides new insights into brain region-dependent AS regulation of the architecture of AD-risk genes that contributes to AD pathologies, ultimately allowing identification of a treatment target and region-specific biomarkers for AD.

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Epigenetic features are significantly associated with alternative splicing.

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Epigenetic features are significantly associated with alternative splicing.

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