Gene isoforms are generated by alternative splicing, in which exons are spliced

and joined together in different combinations. Alternative splicing is an important mechanism of gene function regulation since differences in the mRNA sequences translate into distinct protein domains with distinct roles. Alternative splicing can also affect the 5’ and 3’ UTRs that are essential for gene regulation. Therefore, identifying the transcriptional variants of a gene and the relative abundance of each of them is instrumental to dissecting the functional role of such gene. A large body RGFP966 of evidence has identified alternative splicing differences between ESC and differentiated cell populations [30, 31 and 32•]. Pluripotency regulation by the recently identified novel isoform of FOXP1 in hESCs is a significant landmark exemplifying the importance of alternative splicing and isoform usage [33•]. The annotated FOXP1 isoform (NM_001012505) is important for differentiation, cell proliferation and development [34]. However, a novel exon (18b) was discovered to replace the annotated exon 18 in the traditional isoform NM_001012505, which produces a novel isoform of FOXP1 in hESCs. The alternative exon usage changes the protein coding sequence of the fork-head domain of FOXP1 and consequently changes the DNA-binding specificities resulting in the regulation

of a different set of target genes. This novel isoform is specifically expressed by hESCs and contribute to the regulation of pluripotency genes, such selleck screening library as OCT4, NR5A2 and

NANOG. Novel splice sites, exons and isoforms are also identified in the key pluripotency gene NANOG [35]. Novel 5’ end exons and splices result in various 5’ UTRs and N terminal domains in Nanog. As a result, two protein variants attenuate the self-renewal potential and pluripotency in ESCs. Similarly, novel splices in SALL4 and TCF3 can also change their functions in pluripotency regulation [31 and 32•]. A large body of evidence have identified alternative splicing differences between ESCs and differentiated cell populations [30, 31 and 32•]. These studies, exemplify the importance of large-scale identification of novel isoforms of annotated genes and their abundance, especially for Carbohydrate pluripotency-associated genes. Au et al. reported a few novel isoforms of known pluripotency markers ( Table 1 and Figure 2). For example, in the DPPA4 locus, a RefSeq-annotated isoform is expressed but a novel isoform skipping three exons also contributes to a significant portion (∼17%) of the total gene abundance. In TERT, a novel isoform displaying cassette exon skipping junctions contributes as much as 54% of the gene abundance. Alternative splicing may be one mechanism of regulation of the telomerase activity of TERT.

No related posts.