ExOrthist: a tool to infer exon orthologies at any evolutionary distance

Márquez, Yamile; Mantica, Federica; Cozzuto, Luca; Burguera, Demián; Pulido, Toni Hermoso; Ponomarenko, Julia; Roy, Scott William; Irimia, Manuel

doi:10.1186/s13059-021-02441-9

Cited by 10 publications

(9 citation statements)

References 67 publications

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“…Notwithstanding, 18 additional eMIC-dependent exons in Drosophila and 23 in mouse are present within orthologous genes but at different positions. This recurrence of alternative exons within orthologous genes regulated by the same splicing factor has been previously seen for the epithelial splicing regulatory protein (Esrp)-regulated splicing programs across deuterostomes (62) and, more recently, for Nova-regulated exons between Drosophila and mouse (63), suggesting the presence of hotspots for the evolution of new exons as a common feature in the evolution of splicing programs.…”

Section: Evolution Of Neuronal Emic-regulated Programs In Flies and M...supporting

confidence: 60%

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

et al. 2022

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Alternative splicing increases neuronal transcriptomic complexity throughout animal phylogeny. To delve into the mechanisms controlling the assembly and evolution of this regulatory layer, we characterized the neuronal microexon program in Drosophila and compared it with that of mammals. In nonvertebrate bilaterians, this splicing program is restricted to neurons by the posttranscriptional processing of the enhancer of microexons (eMIC) domain in Srrm234 . In Drosophila , this processing is dependent on regulation by Elav/Fne. eMIC deficiency or misexpression leads to widespread neurological alterations largely emerging from impaired neuronal activity, as revealed by a combination of neuronal imaging experiments and cell type–specific rescues. These defects are associated with the genome-wide skipping of short neural exons, which are strongly enriched in ion channels. We found no overlap of eMIC-regulated exons between flies and mice, illustrating how ancient posttranscriptional programs can evolve independently in different phyla to affect distinct cellular modules while maintaining cell-type specificity.

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Section: Evolution Of Neuronal Emic-regulated Programs In Flies and M...supporting

confidence: 60%

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

et al. 2022

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“…S5 ). To evaluate RetMIC conservation from both the genomic and regulatory perspective, we first derived exon orthologies among all selected vertebrate species using ExOrthist ( 45 ) ( SI Appendix , Methods ). RetMICs showed significantly higher levels of genomic conservation compared to RetLONGs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Specialization of the photoreceptor transcriptome by Srrm3 -dependent microexons is required for outer segment maintenance and vision

Ciampi

Mantica

López-Blanch

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Retinal photoreceptors have a distinct transcriptomic profile compared to other neuronal subtypes, likely reflecting their unique cellular morphology and function in the detection of light stimuli by way of the ciliary outer segment. We discovered a layer of this molecular specialization by revealing that the vertebrate retina expresses the largest number of tissue-enriched microexons of all tissue types. A subset of these microexons is included exclusively in photoreceptor transcripts, particularly in genes involved in cilia biogenesis and vesicle-mediated transport. This microexon program is regulated by Srrm3 , a paralog of the neural microexon regulator Srrm4 . Despite the fact that both proteins positively regulate retina microexons in vitro, only Srrm3 is highly expressed in mature photoreceptors. Its deletion in zebrafish results in widespread down-regulation of microexon inclusion from early developmental stages, followed by other transcriptomic alterations, severe photoreceptor defects, and blindness. These results shed light on the transcriptomic specialization and functionality of photoreceptors, uncovering unique cell type-specific roles for Srrm3 and microexons with implications for retinal diseases.

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“…Lastly, we utilized ExOrthist software 84 to investigate whether a conserved network of genes relies on RBPMS2 -mediated alternative splicing in both zebrafish and human cardiomyocytes. First, genes harboring Rbpms2-regulated splicing events in zebrafish were compared to those in hiPSC-CMs (Figure 6 C).…”

Section: Resultsmentioning

confidence: 99%

RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac Function

Akerberg

Trembley

Butty

et al. 2022

Circulation Research

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Background: RBPs (RNA-binding proteins) perform indispensable functions in the post-transcriptional regulation of gene expression. Numerous RBPs have been implicated in cardiac development or physiology based on gene knockout studies and the identification of pathogenic RBP gene mutations in monogenic heart disorders. The discovery and characterization of additional RBPs performing indispensable functions in the heart will advance basic and translational cardiovascular research. Methods: We performed a differential expression screen in zebrafish embryos to identify genes enriched in nkx2.5 -positive cardiomyocytes or cardiopharyngeal progenitors compared to nkx2.5 -negative cells from the same embryos. We investigated the myocardial-enriched gene RNA-binding protein with multiple splicing (variants) 2 [ RBPMS2 )] by generating and characterizing rbpms2 knockout zebrafish and human cardiomyocytes derived from RBPMS2 -deficient induced pluripotent stem cells. Results: We identified 1848 genes enriched in nkx2.5 -positive population. Among the most highly enriched genes, most with well-established functions in the heart, we discovered the ohnologs rbpms2a and rbpms2b , which encode an evolutionarily conserved RBP. Rbpms2 localizes selectively to cardiomyocytes during zebrafish heart development and strong cardiomyocyte expression persists into adulthood. Rbpms2-deficient embryos suffer from early cardiac dysfunction characterized by reduced ejection fraction. The functional deficit is accompanied by myofibril disarray, altered calcium handling, and differential alternative splicing events in mutant cardiomyocytes. These phenotypes are also observed in RBPMS2 -deficient human cardiomyocytes, indicative of conserved molecular and cellular function. RNA-sequencing and comparative analysis of genes mis-spliced in RBPMS2 -deficient zebrafish and human cardiomyocytes uncovered a conserved network of 29 ortholog pairs that require RBPMS2 for alternative splicing regulation, including RBFOX2 , SLC8A1 , and MYBPC3 . Conclusions: Our study identifies RBPMS2 as a conserved regulator of alternative splicing, myofibrillar organization, and calcium handling in zebrafish and human cardiomyocytes.

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ExOrthist: a tool to infer exon orthologies at any evolutionary distance

Cited by 10 publications

References 67 publications

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

Specialization of the photoreceptor transcriptome by Srrm3 -dependent microexons is required for outer segment maintenance and vision

RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac Function

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