Fig. 1

The paradigmatic splicing regulation mechanisms in precursor messenger RNA (pre-mRNA). Generally, AS has complex correlations with splicing factors, transcriptional machinery (RNA polymerase II elongation rates), and epigenetic modifications (histone marks, epigenetic modifiers, and DNA methylation) at the post- and co-transcriptional levels. During AS process, spliceosome, a highly dynamic ribonucleoprotein complex mainly composed of five different small nuclear ribonucleoprotein (snRNP) complexes (U1, U2, and the tri-snRNP U4/U6. U5 structure), can function in splice sites recognition and reaction on pre-mRNA molecules. The spliceosome assembly process starts with the recognition of the initial 5′ splice site by E complex containing U1 snRNP at the GU motif and the identification of 3′ splice site by three interacting proteins-U2 small nuclear RNA auxiliary factor 1 (U2AF1), U2 small nuclear RNA auxiliary factor 2 (U2AF2), and splicing factor 1 (SF1); then the A complex of U2 snRNP binds to the branch site whose key protein component is splicing factor 3 subunit B1 (SF3B1); finally, the U4/U6. U5 tri-snRNP, forming B complex, triggers the core catalytic reaction of spliceosome. During this process, splicing factors target and interplay with spliceosome components to regulate 5′ and 3′ splice-site recognition flanking the alternative exon, such as serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs). The SR proteins are general splicing activators via binding to exonic/intronic splicing enhancers (E/ISEs) to facilitate exon formation, whereas hnRNPs are general splicing inhibitors via binding to exonic/intronic splicing silencers (E/ISSs) to interfere with the splice site recognition