Where splicing joins chromatin

Jarmila Hnilicová, David Staněk
2011 Nucleus  
The vast majority of our genes has a puzzle-like structure where short coding sequences (exons) must be correctly identified and joined together while surrounding much longer non-coding sequences (introns) have to be removed before a mature mRNA is exported to the cytoplasm and translated. A typical human gene contains 8 introns of average length ~3.4 kb but much larger examples were found (e.g., the last intron of glypican 5 gene is 721 kb in length). 1 In contrast to long introns, exons are
more » ... ort having an average length of 145 bp and represent only a small fraction of primary pre-mRNA transcripts. An extreme example is the largest human gene CNTNAP2 encoding Caspr2 protein which spans over 2.3 Mb (!) but its spliced mRNA is only 10 kb long because 99.6% of the CNTNAP2 gene sequence corresponds to introns. 2 To further complicate matters, exons and introns are not always recognized identically and, for example, a particular exon can be skipped in a fraction of mature mRNAs. This process, called alternative splicing, produces different mRNA isoforms from one gene which significantly increases the coding potential of our genome. It is estimated that in human cells almost 95% of genes are alternatively spliced 3,4 and that there are on average 7 different alternative splicing events per single gene leading to different mRNA variants. 4 The complexity of the process puts There are numerous data suggesting that two key steps in gene expression-transcription and splicing influence each other closely. For a long time it was known that chromatin modifications regulate transcription, but only recently it was shown that chromatin and histone modifications play a significant role in pre-mRNA splicing. Here we summarize interactions between splicing machinery and chromatin and discuss their potential functional significance. We focus mainly on histone acetylation and methylation and potential mechanisms of their role in splicing. It seems that whereas histone acetylation acts mainly by alterating the transcription rate, histone methylation can also influence splicing directly by recruiting various splicing components. Abbreviations: HDAC, histone deacetylase; snRNP, small ribonucleoprotein particle; hnRNP, heterogeneous nuclear ribonucleoprotein pressure on cells to regulate splicing precisely. Then how is alternative splicing regulated? Introns contain consensus splice sites at both ends. However, compared to yeasts, most splice site sequences in higher metazoans are degenerate and additional regulatory sequences in pre-mRNA are needed to help basal splicing machinery (the spliceosome) to recognize correct splice sites. 5 These regulatory sequences are bound by many different splicing regulatory proteins which are able to interact with the splicing complex. The combinatorial interplay among splicing factors results in the usage (or skipping) of individual splice sites. Some of the splicing regulatory proteins are widely expressed in different tissues (such as PTB or SR proteins) while the others are highly tissue specific (for example, Nova proteins are expressed almost exclusively in neurons). The differences in the expression of splicing regulatory proteins are believed to be responsible for tissue-specific alternative splicing. 6 The splicing code-the sum of all splicing related features in a pre-mRNA sequence-can explain a majority of differences in alternative splicing between individual tissues (e.g., 74% out of 97 tested alternative splicing events specific for the central nervous system and muscle tissue were properly predicted based on a pre-mRNA sequence). 7 Although the splicing code model was effective to estimate whether the alternative exon was included or skipped it was less precise in the prediction of the level of inclusion/exclusion when tested by Barash et al. which indicates a presence of additional regulatory signals. 7 Splicing is Cotranscriptional and Occurs in the Vicinity of Chromatin Intron recognition and removal likely occur in the cell nucleus very shortly after intron transcription. Splicing complexes associate with pre-mRNA immediately after the target sequences are synthesized and splicing of many introns is completed before pre-mRNA transcription termination. [8] [9] [10] [11] [12] [13] [14] [15] This was shown not only for long human genes but also for many yeast genes, which are much shorter than human genes and are spliced cotranscriptionally as well. [16] [17] [18] [19] [20] [21] Moreover, splicing can induce pausing of RNA polymerase II during transcription 21 and RNA polymerase II was shown to pause in terminal exons, which increases the time window for cotranscriptional splicing. 16 This suggests that transcription and splicing are coupled not only in time, but also functionally. It was shown that the
doi:10.4161/nucl.2.3.15876 pmid:21818411 pmcid:PMC3149878 fatcat:pzob7wqorjde7bsenkpy7uoolu