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Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types.
Seiler M, Peng S, Agrawal AA, Palacino J, Teng T, Zhu P, Smith PG, Cancer Genome Atlas Research Network, Buonamici S, Yu L
(2018) Cell Rep 23: 282-296.e4
MeSH Terms: Cell Line, Tumor, Genes, Tumor Suppressor, Humans, Loss of Function Mutation, Mutation Rate, Neoplasms, Oncogenes, RNA Splicing, RNA Splicing Factors
Show Abstract · Added October 30, 2019
Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Co-expression networks reveal the tissue-specific regulation of transcription and splicing.
Saha A, Kim Y, Gewirtz ADH, Jo B, Gao C, McDowell IC, GTEx Consortium, Engelhardt BE, Battle A
(2017) Genome Res 27: 1843-1858
MeSH Terms: Bayes Theorem, Databases, Genetic, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Genotyping Techniques, Humans, Organ Specificity, Polymorphism, Single Nucleotide, RNA Splicing, Sequence Analysis, RNA
Show Abstract · Added November 29, 2017
Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues.
© 2017 Saha et al.; Published by Cold Spring Harbor Laboratory Press.
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11 MeSH Terms
Structural and functional analyses of the spliceosome requires a multi-disciplinary approach.
Ohi MD
(2017) Methods 125: 1-2
MeSH Terms: Animals, Humans, RNA Splicing, RNA, Messenger, Ribonucleoproteins, Small Nuclear, Spliceosomes
Added March 3, 2020
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Evidence of selection on splicing-associated loci in human populations and relevance to disease loci mapping.
Gamazon ER, Konkashbaev A, Derks EM, Cox NJ, Lee Y
(2017) Sci Rep 7: 5980
MeSH Terms: Chromosome Mapping, Disease, Genetic Loci, Genetics, Population, Genome-Wide Association Study, Humans, Introns, Nucleotide Motifs, Polymorphism, Single Nucleotide, RNA Splicing, Selection, Genetic
Show Abstract · Added October 27, 2017
We performed a whole-genome scan of genetic variants in splicing regulatory elements (SREs) and evaluated the extent to which natural selection has shaped extant patterns of variation in SREs. We investigated the degree of differentiation of single nucleotide polymorphisms (SNPs) in SREs among human populations and applied long-range haplotype- and multilocus allelic differentiation-based methods to detect selection signatures. We describe an approach, sampling a large number of loci across the genome from functional classes and using the consensus from multiple tests, for identifying candidates for selection signals. SRE SNPs in various SNP functional classes show different patterns of population differentiation compared with their non-SRE counterparts. Intronic regions display a greater enrichment for extreme population differentiation among the potentially tissue-dependent transcript ratio quantitative trait loci (trQTLs) than SRE SNPs in general and includ outlier trQTLs for cross-population composite likelihood ratio, suggesting that incorporation of context annotation for regulatory variation may lead to improved detection of signature of selection on these loci. The proportion of extremely rare SNPs disrupting SREs is significantly higher in European than in African samples. The approach developed here will be broadly useful for studies of function and disease-associated variation in the human genome.
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11 MeSH Terms
Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure.
He KY, Wang H, Cade BE, Nandakumar P, Giri A, Ware EB, Haessler J, Liang J, Smith JA, Franceschini N, Le TH, Kooperberg C, Edwards TL, Kardia SL, Lin X, Chakravarti A, Redline S, Zhu X
(2017) PLoS Genet 13: e1006678
MeSH Terms: Adult, Blood Pressure, Body Mass Index, Chromosomes, Human, Pair 16, European Continental Ancestry Group, Family Health, Female, Gene Expression, Gene Frequency, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, RNA Splicing Factors
Show Abstract · Added April 26, 2017
Many large genome-wide association studies (GWAS) have identified common blood pressure (BP) variants. However, most of the identified BP variants do not overlap with the linkage evidence observed from family studies. We thus hypothesize that multiple rare variants contribute to the observed linkage evidence. We performed linkage analysis using 517 individuals in 130 European families from the Cleveland Family Study (CFS) who have been genotyped on the Illumina OmniExpress Exome array. The largest linkage peak was observed on chromosome 16p13 (MLOD = 2.81) for systolic blood pressure (SBP). Follow-up conditional linkage and association analyses in the linkage region identified multiple rare, coding variants in RBFOX1 associated with reduced SBP. In a 17-member CFS family, carriers of the missense variant rs149974858 are normotensive despite being obese (average BMI = 60 kg/m2). Gene-based association test of rare variants using SKAT-O showed significant association with SBP (p-value = 0.00403) and DBP (p-value = 0.0258) in the CFS participants and the association was replicated in large independent replication studies (N = 57,234, p-value = 0.013 for SBP, 0.0023 for PP). RBFOX1 is expressed in brain tissues, the atrial appendage and left ventricle in the heart, and in skeletal muscle tissues, organs/tissues which are potentially related to blood pressure. Our study showed that associations of rare variants could be efficiently detected using family information.
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19 MeSH Terms
Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression.
Qiao J, Grabowska MM, Forestier-Roman IS, Mirosevich J, Case TC, Chung DH, Cates JM, Matusik RJ, Manning HC, Jin R
(2016) Oncotarget 7: 61955-61969
MeSH Terms: Adenocarcinoma, Androgen Antagonists, Androgens, Antineoplastic Agents, Cell Line, Tumor, Disease Progression, Gastrin-Releasing Peptide, Gene Expression Regulation, Neoplastic, Genetic Variation, Humans, Male, Prostatic Neoplasms, Castration-Resistant, RNA Splicing, Receptors, Androgen, Receptors, Bombesin, Signal Transduction, Transcription, Genetic
Show Abstract · Added April 6, 2017
Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action. Previously, we demonstrated that activation of NF-κB signaling increases ARVs expression in prostate cancer (PC) cells, thereby promoting progression to CRPC. However, it is unclear how NF-κB signaling is activated in CRPC. In this study, we report that long-term treatment with anti-androgens increases a neuroendocrine (NE) hormone - gastrin-releasing peptide (GRP) and its receptor (GRP-R) expression in PC cells. In addition, activation of GRP/GRP-R signaling increases ARVs expression through activating NF-κB signaling. This results in an androgen-dependent tumor progressing to a castrate resistant tumor. The knock-down of AR-V7 restores sensitivity to antiandrogens of PC cells over-expressing the GRP/GRP-R signaling pathway. These findings strongly indicate that the axis of Androgen-Deprivation Therapy (ADT) induces GRP/GRP-R activity, activation NF-κB and increased levels of AR-V7 expression resulting in progression to CRPC. Both prostate adenocarcinoma and small cell NE prostate cancer express GRP-R. Since the GRP-R is clinically targetable by analogue-based approach, this provides a novel therapeutic approach to treat advanced CRPC.
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17 MeSH Terms
Comparative analysis of the GNAQ, GNA11, SF3B1, and EIF1AX driver mutations in melanoma and across the cancer spectrum.
Johnson DB, Roszik J, Shoushtari AN, Eroglu Z, Balko JM, Higham C, Puzanov I, Patel SP, Sosman JA, Woodman SE
(2016) Pigment Cell Melanoma Res 29: 470-3
MeSH Terms: Eukaryotic Initiation Factor-1, GTP-Binding Protein alpha Subunits, GTP-Binding Protein alpha Subunits, Gq-G11, Genes, Neoplasm, Humans, Immunotherapy, Melanoma, Mutation, Mutation, Missense, Neoplasms, Phosphoproteins, Point Mutation, Prognosis, RNA Splicing Factors
Added April 6, 2017
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14 MeSH Terms
Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing.
Kavanaugh G, Zhao R, Guo Y, Mohni KN, Glick G, Lacy ME, Hutson MS, Ascano M, Cortez D
(2015) Mol Cell Biol 35: 2979-90
MeSH Terms: Ataxia Telangiectasia Mutated Proteins, Base Sequence, Cell Cycle Proteins, Cell Line, DNA Damage, DNA Repair, DNA Replication, Gene Expression Profiling, HEK293 Cells, Humans, RNA Interference, RNA Splicing, RNA, Small Interfering, Regulatory Sequences, Nucleic Acid, Sequence Analysis, RNA, Signal Transduction, Stress, Physiological, Transcription Factors
Show Abstract · Added February 4, 2016
Accurate replication of DNA is imperative for the maintenance of genomic integrity. We identified Enhancer of Rudimentary Homolog (ERH) using a whole-genome RNA interference (RNAi) screen to discover novel proteins that function in the replication stress response. Here we report that ERH is important for DNA replication and recovery from replication stress. ATR pathway activity is diminished in ERH-deficient cells. The reduction in ATR signaling corresponds to a decrease in the expression of multiple ATR pathway genes, including ATR itself. ERH interacts with multiple RNA processing complexes, including splicing regulators. Furthermore, splicing of ATR transcripts is deficient in ERH-depleted cells. Transcriptome-wide analysis indicates that ERH depletion affects the levels of ∼1,500 transcripts, with DNA replication and repair genes being highly enriched among those with reduced expression. Splicing defects were evident in ∼750 protein-coding genes, which again were enriched for DNA metabolism genes. Thus, ERH regulation of RNA processing is needed to ensure faithful DNA replication and repair.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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18 MeSH Terms
Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans.
GTEx Consortium
(2015) Science 348: 648-60
MeSH Terms: Alleles, Blood Pressure, Disease, GTPase-Activating Proteins, Gene Expression Regulation, Gene Regulatory Networks, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Multigene Family, Organ Specificity, Pilot Projects, Quantitative Trait Loci, RNA Splicing, RNA, Untranslated, Sequence Analysis, RNA, Tibial Arteries, Transcriptome
Show Abstract · Added April 13, 2017
Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.
Copyright © 2015, American Association for the Advancement of Science.
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20 MeSH Terms
Defective structural RNA processing in relapsing-remitting multiple sclerosis.
Spurlock CF, Tossberg JT, Guo Y, Sriram S, Crooke PS, Aune TM
(2015) Genome Biol 16: 58
MeSH Terms: Autoantigens, Gene Expression, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Humans, Leukocytes, Mononuclear, Multiple Sclerosis, Relapsing-Remitting, Phosphoproteins, Poly A, RNA Splicing, RNA Stability, RNA, Ribosomal, 18S, RNA, Ribosomal, 28S, RNA, Small Cytoplasmic, RNA, Small Interfering, Ribonucleoproteins
Show Abstract · Added April 18, 2017
BACKGROUND - Surveillance of integrity of the basic elements of the cell including DNA, RNA, and proteins is a critical element of cellular physiology. Mechanisms of surveillance of DNA and protein integrity are well understood. Surveillance of structural RNAs making up the vast majority of RNA in a cell is less well understood. Here, we sought to explore integrity of processing of structural RNAs in relapsing remitting multiple sclerosis (RRMS) and other inflammatory diseases.
RESULTS - We employed mononuclear cells obtained from subjects with RRMS and cell lines. We used quantitative-PCR and whole genome RNA sequencing to define defects in structural RNA surveillance and siRNAs to deplete target proteins. We report profound defects in surveillance of structural RNAs in RRMS exemplified by elevated levels of poly(A) + Y1-RNA, poly(A) + 18S rRNA and 28S rRNAs, elevated levels of misprocessed 18S and 28S rRNAs and levels of the U-class of small nuclear RNAs. Multiple sclerosis is also associated with genome-wide defects in mRNA splicing. Ro60 and La proteins, which exist in ribonucleoprotein particles and play different roles in quality control of structural RNAs, are also deficient in RRMS. In cell lines, silencing of the genes encoding Ro60 and La proteins gives rise to these same defects in surveillance of structural RNAs.
CONCLUSIONS - Our results establish that profound defects in structural RNA surveillance exist in RRMS and establish a causal link between Ro60 and La proteins and integrity of structural RNAs.
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16 MeSH Terms