Understanding epigenetic mechanisms in tissue-specific gene expression

Between 20-25,000 protein coding genes have been identified in the human and mouse genomes that give rise to ~200,000 transcripts in tissue- and developmental stage-specific combinations. These transcripts can be generated via co-transcriptional pre-mRNA processing mechanisms that include alternative splicing (AS) and alternative polyadenylation (APA). Estimates based on transcriptome analyses reveal that ~90% of human transcripts undergo AS and that APA occurs in at least 70% of mammalian pre-mRNAs. AS involves the differential inclusion of exons and sometimes introns to form the mature mRNA. APA refers to the polyadenylation of transcripts originating from the same gene but that differ in their 3' end. Both AS and APA are dependent on specific sequences recognised by the cellular machinery. APA events can occur either at 3' untranslated regions (UTRs) or intragenic locations, here we consider intragenic APA. The incidence of intragenic polyadenylation (IPA) varies across tissues and cell types providing a way to diversify both the transcriptome and the proteome. Genome-wide, we have identified over 4000 host genes that harbour an (intragenic CpG island) iCGI in the mammalian genome, including novel iCGI/host gene pairs. The transcriptional activity of these iCGIs is tissue- and developmental stage-specific and, for the first time, we demonstrated that the premature termination of host gene transcripts upstream of iCGIs is closely correlated with the level of iCGI transcription in a DNA-methylation independent manner. These studies suggest that iCGI transcription, rather than histone modification (eg H3K36me3) or DNA methylation, interfere with host gene transcription and pre-mRNA processing genome-wide and contribute to the spatiotemporal diversification and regulation of the transcriptome, impacting proteome. There is evidence in the literature for the failure of correct AS and APA to result in pathological conditions and cancer.
Imprinted genes are...