HBA-DEALS: accurate and simultaneous identification of differential expression and splicing using hierarchical Bayesian analysis

Karlebach, Guy; Hansen, Peter J.; Veiga, Diogo F.T.; Steinhaus, Robin; Daniš, Daniel; Li, Sheng; Anczuków, Olga; Robinson, Peter N.

doi:10.1186/s13059-020-02072-6

Cited by 9 publications

(13 citation statements)

References 58 publications

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“…In addition, differential splicing can modify miRNA-binding sites, especially frequent in 3’UTRs, to change the transcriptome in response to internal or external stimuli [ 42 , 72 ]. Among all genes found to be regulated at the splicing level in this study, many were involved in transcription, RNA processing and splicing, as well as in ribosome biogenesis and in translation, in accordance with previous observations on the main functional categories to which genes that are regulated by AS belong [ 73 ]. Strikingly, we observed a poor correlation between the transcription rate and the AS regulation profile of these genes, suggesting that, most of the time, only isoform ratios were modified.…”

Section: Discussionsupporting

confidence: 92%

Alternative splicing regulation appears to play a crucial role in grape berry development and is also potentially involved in adaptation responses to the environment

et al. 2021

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Background Alternative splicing (AS) produces transcript variants playing potential roles in proteome diversification and gene expression regulation. AS modulation is thus essential to respond to developmental and environmental stimuli. In grapevine, a better understanding of berry development is crucial for implementing breeding and viticultural strategies allowing adaptation to climate changes. Although profound changes in gene transcription have been shown to occur in the course of berry ripening, no detailed study on splicing modifications during this period has been published so far. We report here on the regulation of gene AS in developing berries of two grapevine (Vitis vinifera L.) varieties, Gewurztraminer (Gw) and Riesling (Ri), showing distinctive phenotypic characteristics. Using the software rMATS, the transcriptomes of berries at four developmental steps, from the green stage to mid-ripening, were analysed in pairwise comparisons between stages and varieties. Results A total of 305 differential AS (DAS) events, affecting 258 genes, were identified. Interestingly, 22% of these AS events had not been reported before. Among the 80 genes that underwent the most significant variations during ripening, 22 showed a similar splicing profile in Gw and Ri, which suggests their involvement in berry development. Conversely, 23 genes were subjected to splicing regulation in only one variety. In addition, the ratios of alternative isoforms were different in Gw and Ri for 35 other genes, without any change during ripening. This last result indicates substantial AS differences between the two varieties. Remarkably, 8 AS events were specific to one variety, due to the lack of a splice site in the other variety. Furthermore, the transcription rates of the genes affected by stage-dependent splicing regulation were mostly unchanged, identifying AS modulation as an independent way of shaping the transcriptome. Conclusions The analysis of AS profiles in grapevine varieties with contrasting phenotypes revealed some similarity in the regulation of several genes with developmental functions, suggesting their involvement in berry ripening. Additionally, many splicing differences were discovered between the two varieties, that could be linked to phenotypic specificities and distinct adaptive capacities. Together, these findings open perspectives for a better understanding of berry development and for the selection of grapevine genotypes adapted to climate change.

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Section: Discussionsupporting

confidence: 92%

Alternative splicing regulation appears to play a crucial role in grape berry development and is also potentially involved in adaptation responses to the environment

et al. 2021

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“…To test this hypothesis, we analyzed published data on ER-dependent transcriptional responses in a three-dimensional human breast cell culture model ( 44 ). We performed isoform-level differential splicing analysis using RSEM ( 45 ) and HBA-DEALS ( 46 ). We then computed the overlap between differentially spliced genes for each cell line and genes that contained significant events in breast samples from the GTEx dataset, and combined the hypergeometric p-values using Fisher’s method to obtain a p -value of 2.6 × 10 −5 (table S2).…”

Section: Resultsmentioning

confidence: 99%

“…Paired-end fastq files were downloaded from the SRA, quality-controlled using fastp ( 69 ), and aligned using STAR ( 70 ) via RSEM ( 45 ), following by isoform quantification and differentialsplicing prediction by HBA-DEALS ( 46 ). For each cell line, isoforms that are expressed in all samples were considered expressed, and genes that had at least 2 expressed isoforms were analyzed.…”

Section: Methodsmentioning

confidence: 99%

The impact of biological sex on alternative splicing

Karlebach

Veiga

Mays

et al. 2018

Preprint

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Over 95% of human genes undergo alternative splicing (AS) in a developmental, tissue-specific, or signal transduction-dependent manner. A number of factors including binding of cis-acting sequences by RNA-binding proteins (RBPs) are known to affect AS, but the combinatorial mechanisms leading to the distribution of spliced isoforms remain largely unstudied. Here, in 9011 samples from 532 individuals across 53 tissues from the Genotype-Tissue Expression (GTEx) resource, we identified 4,135 genes with sex-biased expression and 5,925 sex-biased AS events. We find that factors including escape from X-chromosomal inactivation, presence of Alu elements, and oestrogen receptor binding sites affect sex-biased AS. We utilize hierarchical Bayesian modelling to characterize the interactions of exon skipping, gene expression, and RBPs, and demonstrate two categories of sex-biased AS that differ with respect to splice site scores, gene expression, RBP levels, and skipping/inclusion ratio. Alternative splicing (AS), a process by which splice sites are used differentially to create protein diversity, plays an important role in development, 1 disease, 2 and aging. 3 Although some splicing isoforms are produced in the same proportions in all or most cell types, AS is often regulated by developmental or differential cues or in response to external stimuli. 4 Several mechanisms have been demonstrated to regulate AS, although their combinatorial interactions remain poorly understood. Binding of RNA-binding proteins (RBPs) to intronic or exonic cis-acting regulatory sequences may promote or suppress local AS events. 5 Additionally, chromatin-level mechanisms also play a role in AS regulation. Nucleosome density is higher within exons than in introns, suggesting the existence of RNA polymerase II (RNA Pol II)-mediated cross-talk between chromatin structure and exon-intron architecture. 6 Alternative exons with suboptimal splicing signals may require more time to be recognized by the splicing machinery, and faster transcriptional elongation by RNA Pol II may influence exon skipping. 7

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“…We used HBA-DEALS [36] to calculate the probabilities of differential expression and differential splicing. HBA-DEALS automatically determines the hierarchy of the covariates α and β - they are either in the same model layer and predict isoform expression, or β is in a separate layer that predicts gene expression separately.…”

Section: Methodsmentioning

confidence: 99%

Betacoronavirus-specific alternate splicing

Karlebach

et al. 2021

Preprint

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Viruses can subvert a number of cellular processes in order to block innate antiviral responses, and many viruses interact with cellular splicing machinery. SARS-CoV-2 infection was shown to suppress global mRNA splicing, and at least 10 SARS-CoV-2 proteins bind specifically to one or more human RNAs. Here, we investigate 17 published experimental and clinical datasets related to SARS-CoV-2 infection as well as datasets from the betacoronaviruses SARS-CoV and MERS as well as Streptococcus pneumonia, HCV, Zika virus, Dengue virus, influenza H3N2, and RSV. We show that genes showing differential alternative splicing in SARS-CoV-2 have a similar functional profile to those of SARS-CoV and MERS and affect a diverse set of genes and biological functions, including many closely related to virus biology. Additionally, the differentially spliced transcripts of cells infected by coronaviruses were more likely to undergo intron-retention, contain a pseudouridine modification and a smaller number of exons than differentially spliced transcripts in the control groups. Viral load in clinical COVID-19 samples was correlated with isoform distribution of differentially spliced genes. A significantly higher number of ribosomal genes are affected by DAS and DGE in betacoronavirus samples, and the betacoronavirus differentially spliced genes are depleted for binding sites of RNA-binding proteins. Our results demonstrate characteristic patterns of differential splicing in cells infected by SARS-CoV-2, SARS-CoV, and MERS, potentially modifying a broad range of cellular functions and affecting a diverse set of genes and biological functions.

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HBA-DEALS: accurate and simultaneous identification of differential expression and splicing using hierarchical Bayesian analysis

Cited by 9 publications

References 58 publications

Alternative splicing regulation appears to play a crucial role in grape berry development and is also potentially involved in adaptation responses to the environment

Alternative splicing regulation appears to play a crucial role in grape berry development and is also potentially involved in adaptation responses to the environment

The impact of biological sex on alternative splicing

Betacoronavirus-specific alternate splicing

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