Editing RNA splicing (section)

==Alternative splicing==
{{main|Alternative splicing}}

In many cases, the splicing process can create a range of unique proteins by varying the exon composition of the same mRNA. This phenomenon is then called [[alternative splicing]]. Alternative splicing can occur in many ways. Exons can be extended or skipped, or introns can be retained. It is estimated that 95% of transcripts from multiexon genes undergo alternative splicing, some instances of which occur in a tissue-specific manner and/or under specific cellular conditions.<ref>{{cite journal | vauthors = Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ | title = Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing | journal = Nature Genetics | volume = 40 | issue = 12 | pages = 1413–1415 | date = December 2008 | pmid = 18978789 | doi = 10.1038/ng.259 | s2cid = 9228930 }}</ref> Development of high throughput mRNA sequencing technology can help quantify the expression levels of alternatively spliced isoforms. Differential expression levels across tissues and cell lineages allowed computational approaches to be developed to predict the functions of these isoforms.<ref name=Eksi>{{cite journal | vauthors = Eksi R, Li HD, Menon R, Wen Y, Omenn GS, Kretzler M, Guan Y | title = Systematically differentiating functions for alternatively spliced isoforms through integrating RNA-seq data | journal = PLOS Computational Biology | volume = 9 | issue = 11 | pages = e1003314 | date = Nov 2013 | pmid = 24244129 | pmc = 3820534 | doi = 10.1371/journal.pcbi.1003314 | bibcode = 2013PLSCB...9E3314E | doi-access = free }}</ref><ref>{{cite journal | vauthors = Li HD, Menon R, Omenn GS, Guan Y | title = The emerging era of genomic data integration for analyzing splice isoform function | journal = Trends in Genetics | volume = 30 | issue = 8 | pages = 340–347 | date = August 2014 | pmid = 24951248 | pmc = 4112133 | doi = 10.1016/j.tig.2014.05.005 }}</ref>
Given this complexity, alternative splicing of pre-mRNA transcripts is regulated by a system of trans-acting proteins (activators and repressors) that bind to cis-acting sites or "elements" (enhancers and silencers) on the pre-mRNA transcript itself. These proteins and their respective binding elements promote or reduce the usage of a particular splice site. The binding specificity comes from the sequence and structure of the cis-elements, e.g. in HIV-1 there are many donor and acceptor splice sites. Among the various splice sites, ssA7, which is 3' acceptor site, folds into three stem loop structures, i.e. Intronic splicing silencer (ISS), Exonic splicing enhancer (ESE), and Exonic splicing silencer (ESSE3). Solution structure of Intronic splicing silencer and its interaction to host protein hnRNPA1 give insight into specific recognition.<ref>{{cite journal | vauthors = Jain N, Morgan CE, Rife BD, Salemi M, Tolbert BS | title = Solution Structure of the HIV-1 Intron Splicing Silencer and Its Interactions with the UP1 Domain of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1 | journal = The Journal of Biological Chemistry | volume = 291 | issue = 5 | pages = 2331–2344 | date = January 2016 | pmid = 26607354 | pmc = 4732216 | doi = 10.1074/jbc.M115.674564 | doi-access = free }}</ref> However, adding to the complexity of alternative splicing, it is noted that the effects of regulatory factors are many times position-dependent. For example, a splicing factor that serves as a splicing activator when bound to an intronic enhancer element may serve as a repressor when bound to its splicing element in the context of an exon, and vice versa.<ref name="Lim">{{cite journal | vauthors = Lim KH, Ferraris L, Filloux ME, Raphael BJ, Fairbrother WG | title = Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 27 | pages = 11093–11098 | date = July 2011 | pmid = 21685335 | pmc = 3131313 | doi = 10.1073/pnas.1101135108 | doi-access = free | bibcode = 2011PNAS..10811093H }}</ref> In addition to the position-dependent effects of enhancer and silencer elements, the location of the branchpoint (i.e., distance upstream of the nearest 3' acceptor site) also affects splicing.<ref name=Taggart/> The secondary structure of the pre-mRNA transcript also plays a role in regulating splicing, such as by bringing together splicing elements or by masking a sequence that would otherwise serve as a binding element for a splicing factor.<ref>{{cite journal | vauthors = Warf MB, Berglund JA | title = Role of RNA structure in regulating pre-mRNA splicing | journal = Trends in Biochemical Sciences | volume = 35 | issue = 8014 | pages = 169–178 | date = May 2024 | pmid = 19959365 | pmc = 2834840 | doi = 10.1016/j.tibs.2009.10.004 }}</ref><ref>{{cite journal | vauthors = Reid DC, Chang BL, Gunderson SI, Alpert L, Thompson WA, Fairbrother WG | title = Next-generation SELEX identifies sequence and structural determinants of splicing factor binding in human pre-mRNA sequence | journal = RNA | volume = 15 | issue = 12 | pages = 2385–2397 | date = December 2009 | pmid = 19861426 | pmc = 2779669 | doi = 10.1261/rna.1821809 }}</ref>