The human transcriptome comprises >80,000 protein-coding transcripts and the estimated number of proteins synthesized from these transcripts is in the range of 250,000 to 1 million. These transcripts and proteins are encoded by less than 20,000 genes, suggesting extensive regulation at the transcriptional, post-transcriptional, and translational level. Here we review how RNA sequencing (RNA-seq) technologies have increased our understanding of the mechanisms that give rise to alternative transcripts and their alternative translation. We highlight four different regulatory processes: alternative transcription initiation, alternative splicing, alternative polyadenylation, and alternative translation initiation. We discuss their transcriptome-wide distribution, their impact on protein expression, their biological relevance, and the possible molecular mechanisms leading to their alternative regulation. We conclude with a discussion of the coordination and the interdependence of these four regulatory layers.
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