Corepressor diversification by alternative mRNA splicing is species specific

Abstract

BackgroundSMRT and NCoR are corepressor paralogs that help mediate transcriptional repression by a variety of transcription factors, including the nuclear hormone receptors. The functions of both corepressors are extensively diversified in mice by alternative mRNA splicing, generating a series of protein variants that differ in different tissues and that exert different, even diametrically opposite, biochemical and biological effects from one another.ResultsWe report here that the alternative splicing previously reported for SMRT appears to be a relatively recent evolutionary phenomenon, with only one of these previously identified sites utilized in a teleost fish and a limited additional number of the additional known sites utilized in a bird, reptile, and marsupial. In contrast, extensive SMRT alternative splicing at these sites was detected among the placental mammals. The alternative splicing of NCoR previously identified in mice (and shown to regulate lipid and carbohydrate metabolism) is likely to have arisen separately and after that of SMRT, and includes an example of convergent evolution.ConclusionsWe propose that the functions of both SMRT and NCoR have been diversified by alternative splicing during evolution to allow customization for different purposes in different tissues and different species.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-016-0781-2) contains supplementary material, which is available to authorized users.

A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair

“…36 The appearance of this isoform in placentals may reflect functional requirements unique to placental mammals, as is the case for other chromatin modifiers. 37 Interestingly, the alternative acceptor site for BAP1D scores almost as high as the one for BAP1FL, and therefore, exonic splicing enhancers 38 may possibly play a role in the differential expression. BAP1D was still able to enter the nucleus; therefore, a possible mechanim of action is interference with BAP1FL dimerization with ASLX1 39 and consequent inactivation.…”

Evidence fromAmphioxusfor acquisition of alternative mRNA splicing of NCoR corepressor after its duplication and divergence during vertebrate evolution

“…Relatively simple patterns of alternative NCoR-1 and NCoR-2 splicing occur in the more ancient vertebrate taxa, with these patterns conserved and yet more elaborate forms of alternative-splicing added in more recently evolved species [24,35,36]. Overall, three sites of alternative-splicing have been characterized in detail in vertebrate NCoR-1 (exon 28+/28-, exon 37b+/37b-, exon 45a+/45a-/45-) and five in vertebrate NCoR-2 (exon 28+/28-, exon 40b+40/b-, exon 44+/44-, exon 45+/45-, and exon 47b+/47b-/47-) (Figure 1A) [36].…”

“…In contrast the NCoR-1 exon 37b+/37b- and NCoR-2 exon 40b+/40b-alternative-splicing events map within overlapping, interrelated sequences within these two paralogs and insert or omit a conserved “ID3” domain in both that controls their interaction with their nuclear receptor/transcription factor partners. The NCoR-1 exon 37b+/37b-alternative-splice is observed exclusively in placental mammals whereas the NCoR-2 exon 40b+/40b-is present in all vertebrates examined [35,36]. Although this is suggestive of a later evolutionary acquisition of the former, and thus convergent evolution, it was also possible that these alternative-splice events preceded the NCoR duplication event but were selectively lost in NCoR-1 until their reappearance later in evolution [24].…”

“…The PCR products from each primer pair were resolved by electrophoresis in a 2% agarose gel in 1X Tris-Acetate-Ethylenediaminetetraacetate buffer, the DNA bands were visualized with ethidium bromide, and were documented by use of a digital camera. NCoR-2 was previously referred to as SMRT (an alternative nomenclature); the exon numbering system here is as in [35].…”

“…Notably both NCoR-1 and NCoR-2 mRNAs are alternatively-spliced in vertebrates to generate a series of distinct corepressor variants (Figure 1A, internal white rectangles) [25-27]; different alternatively-spliced corepressor variants differ in their biochemical properties, engage in different transcription factor partnerships, exhibit different responses to a variety of cellular signaling pathways, and play different, even opposing biological roles [16,28-34]. Comparisons of different taxa suggest that many of these alternative-splicing events arose separately in NCoR-1 and NCoR-2 [35,36]; nonetheless certain of these alternative-splicing events have closely related features that may be indicative of either a retained ancestral splicing event or representative of convergent evolution [24]. To better understand the origins of these events, an examination of alternative-splicing was undertaken in the single NCoR locus found in Amphioxus (Figure 1B), a cephalochordate generally thought to be closely related to the ancestral organisms that gave rise to the vertebrate lineage (Figure 2) [37-40].…”