Academic journal article Genetics

ALG-1 Influences Accurate mRNA Splicing Patterns in the Caenorhabditis Elegans Intestine and Body Muscle Tissues by Modulating Splicing Factor Activities

Academic journal article Genetics

ALG-1 Influences Accurate mRNA Splicing Patterns in the Caenorhabditis Elegans Intestine and Body Muscle Tissues by Modulating Splicing Factor Activities

Article excerpt

MULTICELLULAR organisms have evolved complex forms of gene regulation achieved at different stages throughout development, and equally executed at pre-, co-, and post-transcriptional levels. Alternative splicing, which leads to the production of different protein isoforms using single mRNA precursors, fine tunes these regulatory networks and contributes to the acquisition oftissue identity and function. In humans, >95% of genes undergo alternative splicing (Pan et al 2008; Wang et al 2008), and this mechanism is required to ensure that each tissue possesses the correct gene expression pattern needed to thrive (Baralle and Giudice 2017). Many aberrant alternative splicing events are linked to diseases (Scotti and Swanson 2016; Montes et al. 2019).

While several tissue-specific splicing factors are known to directly promote RNA splicing, most of the alternative splicing events are achieved through differential expression of particular classes of RNA-binding proteins (RBPs), which in turn bind specific cis-acting elements located within exon/intron junctions in a combinatorial manner, promoting or inhibiting splicing. Serine Arginine (SR) proteins recognize exon-splicing enhancers (ESEs) and are important in promoting constitutive and alternative pre-mRNA splicing, while heterogeneous nuclear ribonucleoproteins (hnRNPs) are a large class of nuclear RBPs that bind exon-splicing silencers (ESSs) and usually promote exon retention (Matlin et al. 2005). The relative expression levels of members from these two classes of splicing factors vary between tissues, and this imbalance is believed to promote the outcome of tissue-specific alternative splicing events (Caceres et al 1994; Zhu et al. 2001).

Tissue identity is also achieved through post-transcriptional gene regulation events, mostly occurring through 3' untranslated regions (3'UTRs), which are portions of genes located between the STOP codon and the poly(A) tail of mature eukaryotic mRNAs. 3'UTRs have been recently subjected to intense study as they were found to be targeted by a variety of factors, which recognize small regulatory elements in these regions and are able to modulate the dosage of gene output at the post-transcriptional level (Matoulkova et al. 2012; Oikonomou et al. 2014; Mayr 2017). While these regulatory mechanisms are still poorly characterized, and the majority of functional elements remain unknown, disorders in the 3' end processing of mRNAs have been found to play key roles in the loss of tissue identity and the establishment of major diseases, including neurodegenerative diseases, diabetes, and cancer (Conne et al. 2000; Mayr and Bartel 2009; Delay et al. 2011; Rehfeld et al. 2013).

3' UTRs are frequently targeted by a class of repressive molecules named microRNAs (miRNAs). miRNAs are short noncoding RNAs, ~22 nt in length, that are incorporated into a large protein complex named the microRNA-induced silencing complex (miRISC), where they guide the interaction between the miRISC and the target mRNA by base pairing, primarily within the 3'UTR (Bartel 2009). The final outcome of miRNA targeting can be context-dependent; however, mRNAs targeted by the miRISC are typically held in translational repression prior to degradation of the transcript (Ambros and Ruvkun 2018; Bartel 2018). Initial studies showed that although mismatches between miRNAs and their targets are common, many interactions make use of perfect complementarity at a small conserved heptametrical motif located at position 2-7 at the 5' end of the miRNA (seed region) (Ambros and Ruvkun 2018; Bartel 2018). Later findings showed that while important, the seed region may also contain one or more mismatches while pairing with its target mRNA, and that this element alone is not a sufficient predictor of miRNA targeting (Ha et al. 1996; Reinhart et al. 2000; Didiano and Hobert 2006; Grimson et al. 2007). Compensatory base pairing at the 3' end of the miRNA (nucleotides 10-13) can also play a role in target recognition (Shin et al. …

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