Drift and conservation of differential exon usage across tissues in primate species

Reyes, Alejandro; Anders, Simon; Weatheritt, Robert J.; Gibson, Toby J.; Steinmetz, Lars M.; Huber, Wolfgang

doi:10.1073/pnas.1307202110

Cited by 118 publications

(118 citation statements)

References 42 publications

(53 reference statements)

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“…10a). For each editing site, to test whether its usage changes more strongly between tissues or between species, we quantified the explained variance by fitting an ANOVA model to each site with tissue and species as explanatory variables and used the sum of squares as the measure of variation 52 .…”

Section: Methodsmentioning

confidence: 99%

Dynamic landscape and regulation of RNA editing in mammals

Tan

Shanmugam

et al. 2017

Nature

500

628

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Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2–7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8–10. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.

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Section: Methodsmentioning

confidence: 99%

Dynamic landscape and regulation of RNA editing in mammals

Tan

Shanmugam

et al. 2017

Nature

500

628

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“…This finding has made researchers question the functionality of the multiple isoforms found, some of which could result from transcriptional noise. Recent research analyzing tissue-specific transcriptomes in different primate species has reinforced the idea that only a subset of the existing alternative splicing events may participate in tissue-specific functions, as evidenced by the conservation of splicing patterns across species (214).…”

Section: Participation Of Transcriptional Coupling In Tissue-specificmentioning

confidence: 99%

Regulation of Alternative Splicing Through Coupling with Transcription and Chromatin Structure

Naftelberg

Schor²,

Ast³

et al. 2015

Annu. Rev. Biochem.

391

354

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Alternative precursor messenger RNA (pre-mRNA) splicing plays a pivotal role in the flow of genetic information from DNA to proteins by expanding the coding capacity of genomes. Regulation of alternative splicing is as important as regulation of transcription to determine cell- and tissue-specific features, normal cell functioning, and responses of eukaryotic cells to external cues. Its importance is confirmed by the evolutionary conservation and diversification of alternative splicing and the fact that its deregulation causes hereditary disease and cancer. This review discusses the multiple layers of cotranscriptional regulation of alternative splicing in which chromatin structure, DNA methylation, histone marks, and nucleosome positioning play a fundamental role in providing a dynamic scaffold for interactions between the splicing and transcription machineries. We focus on evidence for how the kinetics of RNA polymerase II (RNAPII) elongation and the recruitment of splicing factors and adaptor proteins to chromatin components act in coordination to regulate alternative splicing.

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“…For the intron retention analysis, RNA-seq reads were mapped to the current human genome (GRCh38) using Hisat 2 (58). Differential intron retention analysis was carried out in R was using DexSeq package (59,60). In DexSeq the difference of intron inclusion were determined based the counts from the intron and the counts from the two adjacent exons.…”

Section: Rt-qpcrmentioning

confidence: 99%

Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing factor PRPF4B as a metastasis driver

Koedoot

Fokkelman

Rogkoti

et al. 2018

Preprint

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Metastasis is the major cause of death in cancer patients and migration of cancer cells from the primary tumor to distant sites is the prerequisite of metastasis formation. Here we applied an imaging-based RNAi phenotypic cell migration screen using two highly migratory basal breast cancer cell lines (Hs578T and MDA-MB-231) to provide a repository for signaling determinants that functionally drive cancer cell migration. We screened ~4,200 individual target genes covering most cell signaling components and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, of which 43 genes were common denominators of cell migration. Interaction networks of candidate migratory modulators were in common with networks of different clinical breast cancer prognostic and metastasis classifiers. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF were amplified in human primary breast tumors and the expression was associated with metastasisfree survival. Depletion of PRPF4B, BUD31 and BPTF caused primarily down-regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B was essential for triple negative breast cancer cell migration and critical for breast cancer metastasis formation in vivo, making PRPF4B a candidate for further drug development. Our systematic phenotypic screen provides an important repository of candidate metastasis drug targets.

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Drift and conservation of differential exon usage across tissues in primate species

Cited by 118 publications

References 42 publications

Dynamic landscape and regulation of RNA editing in mammals

Dynamic landscape and regulation of RNA editing in mammals

Regulation of Alternative Splicing Through Coupling with Transcription and Chromatin Structure

Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing factor PRPF4B as a metastasis driver

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