Abstract
Muscleblind-like splicing regulators (MBNLs) activate or repress the inclusion of alternative splicing (AS) events, enabling the developmental transition of fetal mRNA splicing isoforms to their adult forms. Herein, we sought to elaborate the mechanism by which MBNLs mediate AS related to biological processes. We evaluated the functional role of DEAD-box (DDX) RNA helicases, DDX5 and DDX17 in MBNL-dependent AS regulation. Whole-transcriptome analysis and validation approaches revealed a handful of MBNLs-dependent AS events to be affected by DDX5 and DDX17 in mostly an opposite manner. The opposite expression patterns of these two groups of factors during muscle development and coordination of fetal-to-adult splicing transition indicate the importance of these proteins at early stages of development. The identified pathways of how the helicases modulate MBNL splicing activity include DDX5 and DDX17-dependent changes in the ratio of MBNL splicing isoforms and most likely changes in accessibility of MBNL-binding sites. Another pathway involves the mode of action of the helicases independent of MBNL activity. These findings lead to a deeper understanding of the network of interdependencies between RNA-binding proteins and constitute a valuable element in the discussion on developmental homeostasis and pathological states in which the studied protein factors play a significant role.
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Introduction
Alternative splicing (AS) is a complex process that contributes to profound diversity of the transcriptome and, consequently, homeostasis of the cellular proteome in response to various stimuli, including environmental, developmental and tissue-specific stimuli [1,2,13]. Nevertheless, their biological expression differs with MBNL1 playing a major function in muscular and immune system development where its expression prevails [14,15,15, 21]. MBNL2 is prominently expressed in the brain and is crucial in neurogenesis [13, 22]. All MBNL paralogs can regulate the inclusion or exclusion of the same AS events with different activities [9]. Additionally, each paralog is represented by a subset of splicing isoforms that differ in the presence of regions encoded by alternative exons (e; e1, e3, e5, e7, e8) [23]. These exons convey distinct properties including intracellular localization [24], RNA-RNA binding efficiency [25], protein–protein interaction [26] or homo-typic interactions [7, 27]. Different splicing activity of the paralogs and isoforms seems to be important during developmental processes as well as in pathological states such as tumorigenesis and multisystem diseases, including myotonic dystrophy types 1 and 2 (DM1 and DM2) [7,8,9, 28].
Multiple research groups have mutually proposed the specific recognition of an RNA motif consisting of a GpC dinucleotide flanked by pyrimidines, YGCY (Y–U or C), by all three MBNL paralogs [9, 29]. The numbers of these motifs close to one another, the secondary structures they are encompassed in and their locations within pre-mRNAs constitute significant determinants of MBNL splicing activity [30, 31]. Interaction of MBNLs with multiple YGCY motifs within an alternative exon or up to 300 nucleotides upstream induces skip** of the exon (e_OFF). This may occur when the association of U2 auxiliary factor 65 kDa subunit (U2AF65) with the 3’ss is impeded through RNA structural changes or steric hindrance, as was shown for TNNT2 e5 [32]. On the other hand, binding of MBNLs within 500 nucleotides of a downstream intron promotes the inclusion of an alternative exon (e_ON) into mRNAs [29], potentially due to an effect on spliceosome formation by the enhancement of U2AF65 binding, as was proposed in studies on the inclusion of INSR e7 [33].
The mechanism by which MBNLs mediate the inclusion or skip** of AS events is strongly expected to be complex and still little is known in this matter. The regulation of AS events has been described between MBNL and other RBPs including DDX helicases [34]. Interestingly, MBNL splicing activity relies on the secondary structure of RNA cis-acting regulatory elements [30, 31], whereas RNA helicases modulate the structural organization of pre-mRNA. It is unclear, however, to what extent the helicases impact MBNL-dependent splicing and whether it has a biological relevance. Until now, two paralogs, DDX5 and DDX17 (DDX5,17) have been shown to coimmunoprecipitate with MBNL1 under weak ionic conditions [35], and DDX5 was found to facilitate MBNL1-induced exclusion of TNNT2 e5 by structurally changing the availability of MBNL-binding sites [34]. Similar to MBNLs, DDX5,17 have been described as important players in the regulation of AS [36,37,38,39] and other molecular pathways that direct developmental processes, including adipogenesis [40], myoblast differentiation [37, 41], neurogenesis [42] and pluripotency determination [78, 79], while MBNL1 isoforms have been found to differently affect cancer cell viability and migration [7]. It would be of great value to investigate whether the relationship between studied RBPs characterizes and shapes tumorigenesis.
Data Availability
Data supporting this study are included within the article and supporting materials.
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Acknowledgements
The authors wish to thank Michał Sekrecki for providing biological materials.
Funding
This work was supported by the Foundation for Polish Science TEAM program co-financed by the European Union within the European Regional Development Fund (POIR.04.04.00-00-5C0C/17-00 to KS), Polish National Science Centre (2017/24/C/NZ1/00112 and 2020/39/D/NZ3/01658 to KT and 2020/38/A/NZ3/00498 to KS), Muscular Dystrophy Association (MDA546770 to ŁJS) and the Ministry of Science and Higher Education of the Republic of Poland, from the quality-promoting subsidy, under the Leading National Research Centre (KNOW) program for the years 2012–2017 (KNOW RNA Research Centre in Poznan; 01/KNOW2/2014). Funding for open access charge: Initiative of Excellence–Research University (05/IDUB/2019/94) at Adam Mickiewicz University, Poznan, Poland.
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KT, KS contributed to conceptualization; KT, KS contributed to funding acquisition; KT, AP, AK, ŁJS, AB, KDR, MPE, CFB, AJ, MB contributed to investigation; KT, KS, ŁJS contributed to methodology; KT wrote the manuscript with editing contributions from KS and ŁJS.
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Taylor, K., Piasecka, A., Kajdasz, A. et al. Modulatory role of RNA helicases in MBNL-dependent alternative splicing regulation. Cell. Mol. Life Sci. 80, 335 (2023). https://doi.org/10.1007/s00018-023-04927-0
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DOI: https://doi.org/10.1007/s00018-023-04927-0