Differential contribution of transcriptomic regulatory layers in the definition of neuronal identity

Ha, Kevin C.H.; Sterne-Weiler, Timothy; Morris, Quaid; Weatheritt, Robert J.; Blencowe, Benjamin J.

doi:10.1038/s41467-020-20483-8

Cited by 28 publications

(15 citation statements)

References 79 publications

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“…Hence, gene expression alone is unlikely to explain the heterogeneous expansion in complexity (as defined by the number of cell types) across vertebrate evolution. Instead, it is becoming increasingly evident that the plethora of posttranscriptional mechanisms (Cheetham et al, 2020;Fiszbein et al, 2019;Gueroussov et al, 2017;Ha et al, 2018;Mattick, 2018;Fiszbein et al, 2019;Cheetham et al, 2020;Ha et al, 2021) capable of greatly expanding transcriptomic diversity also underlies these advances. Among these, an intriguing class produced by pre-mRNA processing are circular RNAs (circR-NAs) (Memczak et al, 2013;Zhang et al, 2013;Li et al, 2018b;Gokool et al, 2020b).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary dynamics of circular RNAs in primates

Santos-Rodriguez

Voineagu

Weatheritt

2021

eLife

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Many primate genes produce circular RNAs (circRNAs). However, the extent of circRNA conservation between closely related species remains unclear. By comparing tissue-specific transcriptomes across over 70 million years of primate evolution, we identify that within 3 million years circRNA expression profiles diverged such that they are more related to species identity than organ type. However, our analysis also revealed a subset of circRNAs with conserved neural expression across tens of millions of years of evolution. By comparing to species-specific circRNAs, we identified that the downstream intron of the conserved circRNAs display a dramatic lengthening during evolution due to the insertion of novel retrotransposons. Our work provides comparative analyses of the mechanisms promoting circRNAs to generate increased transcriptomic complexity in primates.

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Section: Introductionmentioning

confidence: 99%

Evolutionary dynamics of circular RNAs in primates

Santos-Rodriguez

Voineagu

Weatheritt

2021

eLife

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“…Finally, based on the PSI values, we used the diff tool module of vast-tools software with its default parameters to perform a Bayesian inference-based differential AS analysis. The threshold of significance was set at the minimum value for absolute value of differential PSI between MS cases and controls (MV|ΔPSI|) at 0.95 confidence level greater than 10% according to the previous studies ( Fagg et al, 2020 ; Ha et al, 2021 ; Hekman et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data

Huang

Tang

et al. 2021

Front. Genet.

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Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelinating lesions in the central nervous system. Recently, the dysregulation of alternative splicing (AS) in the brain has been found to significantly influence the progression of MS. Moreover, previous studies demonstrate that many MS-related variants in the genome act as the important regulation factors of AS events and contribute to the pathogenesis of MS. However, by far, no genome-wide research about the effect of genomic variants on AS events in MS has been reported. Here, we first implemented a strategy to obtain genomic variant genotype and AS isoform average percentage spliced-in values from RNA-seq data of 142 individuals (51 MS patients and 91 controls). Then, combing the two sets of data, we performed a cis-splicing quantitative trait loci (sQTLs) analysis to identify the cis-acting loci and the affected differential AS events in MS and further explored the characteristics of these cis-sQTLs. Finally, the weighted gene coexpression network and gene set enrichment analyses were used to investigate gene interaction pattern and functions of the affected AS events in MS. In total, we identified 5835 variants affecting 672 differential AS events. The cis-sQTLs tend to be distributed in proximity of the gene transcription initiation site, and the intronic variants of them are more capable of regulating AS events. The retained intron AS events are more susceptible to influence of genome variants, and their functions are involved in protein kinase and phosphorylation modification. In summary, these findings provide an insight into the mechanism of MS.

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“…According to the previous studies, we set the threshold for significance at the minimum value for absolute value of differential PSI between GBM and LGG samples (MV|ΔPSI|) at 0.95 confidence level greater than 10% (Ha et al, 2021;Hekman et al, 2021). The gene annotation was conducted by g:Profiler toolset, a web server for conversions between gene identifiers and functional annotation (Raudvere et al, 2019).…”

Section: Differential Analysis Of Alternative Splicing Events and Ann...mentioning

confidence: 99%

Genome-Wide Analysis for the Regulation of Gene Alternative Splicing by DNA Methylation Level in Glioma and its Prognostic Implications

Yang

Wang

et al. 2022

Front. Genet.

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Glioma is a primary high malignant intracranial tumor with poorly understood molecular mechanisms. Previous studies found that both DNA methylation modification and gene alternative splicing (AS) play a key role in tumorigenesis of glioma, and there is an obvious regulatory relationship between them. However, to date, no comprehensive study has been performed to analyze the influence of DNA methylation level on gene AS in glioma on a genome-wide scale. Here, we performed this study by integrating DNA methylation, gene expression, AS, disease risk methylation at position, and clinical data from 537 low-grade glioma (LGG) and glioblastoma (GBM) individuals. We first conducted a differential analysis of AS events and DNA methylation positions between LGG and GBM subjects, respectively. Then, we evaluated the influence of differential methylation positions on differential AS events. Further, Fisher’s exact test was used to verify our findings and identify potential key genes in glioma. Finally, we performed a series of analyses to investigate influence of these genes on the clinical prognosis of glioma. In total, we identified 130 glioma-related genes whose AS significantly affected by DNA methylation level. Eleven of them play an important role in glioma prognosis. In short, these results will help to better understand the pathogenesis of glioma.

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Differential contribution of transcriptomic regulatory layers in the definition of neuronal identity

Cited by 28 publications

References 79 publications

Evolutionary dynamics of circular RNAs in primates

Evolutionary dynamics of circular RNAs in primates

Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data

Genome-Wide Analysis for the Regulation of Gene Alternative Splicing by DNA Methylation Level in Glioma and its Prognostic Implications

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