Dissecting the transcriptional regulatory networks of promoter-associated noncoding RNAs in development and cancer

Abstract

In-depth analysis of global RNA sequencing has enabled a comprehensive overview of cellular transcriptomes and revealed the pervasive transcription of divergent RNAs from promoter regions across eukaryotic genomes. These studies disclosed that genomes encode a vast repertoire of RNAs beyond the well-known protein-coding messenger RNAs. Furthermore, they have provided novel insights into the regulation of eukaryotic epigenomes, and transcriptomes, including the identification of novel classes of noncoding transcripts, such as the promoter-associated noncoding RNAs (pancRNAs).PancRNAs are defined as transcripts transcribed within few hundred bases from the transcription start sites (TSSs) of protein-coding or non-coding genes. Unlike the long trans-acting ncRNAs that regulate expression of target genes located in different chromosomal domains and displaying their function both in the nucleus and in the cytoplasm, the pancRNAs operate as cis-acting elements in the transcriptional regulation of neighboring genes. PancRNAs are very recently emerging as key players in the epigenetic regulation of gene expression programs in development and diseases.Herein, we review the complex epigenetic network driven by pancRNAs in eukaryotic cells, their impact on physiological and pathological states, which render them promising targets for novel therapeutic strategies.

Keywords: Cancer; Chromatin remodeling; Development; Epigenome; Promoter-associated noncoding RNA (pancRNA).

Fig. 1

Hypothetical models to explain sense and antisense pancRNA (AS pancRNA) activities. a pancRNAs act in concert with PARP1 and TET3 factors to establish the hypomethylated state of CpG islands within the promoter, thus activating in cis the transcription of the host gene. b AS pancRNAs recruit Polycomb repressive complex PRC2, catalyzing the trimethylation of histone H3 at K27 and the chromatin packaging. c AS pancRNAs can bind histone acetylases and methylases that open the chromatin, allowing the engagement of the Mediator Complex and the chromatin looping. d Antisense pancRNAs tight on the promoter an epigenetic silencing complex formed by Ago-1, DNMT3a, EZH2, Suv39H1 and HDAC1, which causes trimethylation of histone H3 at K27, heterochromatin formation and repression of transcription. e pancRNAs can bind RNA binding proteins (including FUS/TLS and Sam68), thus promoting inhibition of the histone acetyltransferase activity of the p300/CREB binding protein (CBP)-associated factor (PCAF) and resulting in the suppression of transcription