CamoTSS: analysis of alternative transcription start sites for cellular phenotypes and regulatory patterns from 5’ scRNA-seq data

Hou, Ruiyan; Hon, Chung-Chau; Huang, Yuanhua

doi:10.1101/2023.04.17.536840

Cited by 2 publications

(2 citation statements)

References 49 publications

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“…Indeed, 83% of genes expressed in the long-read dataset are regulated in a tissue-specific manner, such that they use distinct isoforms across tissues. It is also known that tissue-or context-specific regulation of alternative TSSs or PASs results in global shifts towards preferential usage of upstream or downstream sites 17,[42][43][44][45][46] . And even among dualT genes there is usually one predominant isoform expressed, likely due to tissue-specific regulation of isoform usage and gene expression.…”

Section: Pita Is Independent Of Tissue-specific Mrna Regulationmentioning

confidence: 99%

mRNA initiation and termination are spatially coordinated

Calvo-Roitberg,

Carroll,

Venev

et al. 2024

Preprint

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The expression of a precise mRNA transcriptome is crucial for establishing cell identity and function, with dozens of alternative isoforms produced for a single gene sequence. The regulation of mRNA isoform usage occurs by the coordination of co-transcriptional mRNA processing mechanisms across a gene. Decisions involved in mRNA initiation and termination underlie the largest extent of mRNA isoform diversity, but little is known about any relationships between decisions at both ends of mRNA molecules. Here, we systematically profile the joint usage of mRNA transcription start sites (TSSs) and polyadenylation sites (PASs) across tissues and species. Using both short and long read RNA-seq data, we observe that mRNAs preferentially using upstream TSSs also tend to use upstream PASs, and congruently, the usage of downstream sites is similarly paired. This observation suggests that mRNA 5' end choice may directly influence mRNA 3' ends. Our results suggest a novel "Positional Initiation-Termination Axis" (PITA), in which the usage of alternative terminal sites are coupled based on the order in which they appear in the genome. PITA isoforms are more likely to encode alternative protein domains and use conserved sites. PITA is strongly associated with the length of genomic features, such that PITA is enriched in longer genes with more area devoted to regions that regulate alternative 5' or 3' ends. Strikingly, we found that PITA genes are more likely than non-PITA genes to have multiple, overlapping chromatin structural domains related to pairing of ordinally coupled start and end sites. In turn, PITA coupling is also associated with fast RNA Polymerase II (RNAPII) trafficking across these long gene regions. Our findings indicate that a combination of spatial and kinetic mechanisms couple transcription initiation and mRNA 3' end decisions based on ordinal position to define the expression mRNA isoforms.

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Section: Pita Is Independent Of Tissue-specific Mrna Regulationmentioning

confidence: 99%

mRNA initiation and termination are spatially coordinated

Calvo-Roitberg,

Carroll,

Venev

et al. 2024

Preprint

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“…Tools for the detection and analysis of alternative transcription start sites and alternative polyadenylation sites are sparser than AES tools, though APA tools have been released with increasing frequency in recent years. For transcription start site detection and analysis CAGEfightR and TSRexploreR are known quantities, with SEASTAR, mountainClimber (RNA-seq data) and CamoTSS (scRNA-seq data) tailored towards alternative start site detection and usage rates [62,[144][145][146][147]. We were unable to find any benchmarking studies for tools geared towards alternative transcription start sites.…”

Section: Genome-wide Profiling Of Rna Variants: Challenges and Solutionsmentioning

confidence: 99%

Alternative Transcripts Diversify Genome Function for Phenome Relevance to Health and Diseases

Carrion,

Michal,

Jiang

2023

Genes

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Manipulation using alternative exon splicing (AES), alternative transcription start (ATS), and alternative polyadenylation (APA) sites are key to transcript diversity underlying health and disease. All three are pervasive in organisms, present in at least 50% of human protein-coding genes. In fact, ATS and APA site use has the highest impact on protein identity, with their ability to alter which first and last exons are utilized as well as impacting stability and translation efficiency. These RNA variants have been shown to be highly specific, both in tissue type and stage, with demonstrated importance to cell proliferation, differentiation and the transition from fetal to adult cells. While alternative exon splicing has a limited effect on protein identity, its ubiquity highlights the importance of these minor alterations, which can alter other features such as localization. The three processes are also highly interwoven, with overlapping, complementary, and competing factors, RNA polymerase II and its CTD (C-terminal domain) chief among them. Their role in development means dysregulation leads to a wide variety of disorders and cancers, with some forms of disease disproportionately affected by specific mechanisms (AES, ATS, or APA). Challenges associated with the genome-wide profiling of RNA variants and their potential solutions are also discussed in this review.

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CamoTSS: analysis of alternative transcription start sites for cellular phenotypes and regulatory patterns from 5’ scRNA-seq data

Cited by 2 publications

References 49 publications

mRNA initiation and termination are spatially coordinated

mRNA initiation and termination are spatially coordinated

Alternative Transcripts Diversify Genome Function for Phenome Relevance to Health and Diseases

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