Deep sequencing reveals a novel class of bidirectional promoters associated with neuronal genes

Comprehensive annotation of transcripts expressed in a given tissue is a critical step towards the understanding of regulatory and functional pathways that shape the transcriptome.

Here, we reconstructed a cumulative transcriptome of the human prefrontal cortex (PFC) based on approximately 300 million strand-specific RNA sequence (RNA-seq) reads collected at different stages of postnatal development. We find that more than 50% of reconstructed transcripts represent novel transcriptome elements, including 8,343 novel exons and exon extensions of annotated coding genes, 11,217 novel antisense transcripts and 29,541 novel intergenic transcripts or their fragments showing canonical features of long non-coding RNAs (lncRNAs). Our analysis further led to a surprising discovery of a novel class of bidirectional promoters (NBiPs) driving divergent transcription of mRNA and novel lncRNA pairs and displaying a distinct set of sequence and epigenetic features. In contrast to known bidirectional and unidirectional promoters, NBiPs are strongly associated with genes involved in neuronal functions and regulated by neuron-associated transcription factors.

Taken together, our results demonstrate that large portions of the human transcriptome remain uncharacterized. The distinct sequence and epigenetic features of NBiPs, as well as their specific association with neuronal genes, further suggest existence of regulatory pathways specific to the human brain.