An in-depth map of polyadenylation sites in cancer

Abstract

We present a comprehensive map of over 1 million polyadenylation sites and quantify their usage in major cancers and tumor cell lines using direct RNA sequencing. We built the Expression and Polyadenylation Database to enable the visualization of the polyadenylation maps in various cancers and to facilitate the discovery of novel genes and gene isoforms that are potentially important to tumorigenesis. Analyses of polyadenylation sites indicate that a large fraction (∼30%) of mRNAs contain alternative polyadenylation sites in their 3′ untranslated regions, independent of the cell type. The shortest 3′ untranslated region isoforms are preferentially upregulated in cancer tissues, genome-wide. Candidate targets of alternative polyadenylation-mediated upregulation of short isoforms include POLR2K, and signaling cascades of cell–cell and cell–extracellular matrix contact, particularly involving regulators of Rho GTPases. Polyadenylation maps also helped to improve 3′ untranslated region annotations and identify candidate regulatory marks such as sequence motifs, H3K36Me3 and Pabpc1 that are isoform dependent and occur in a position-specific manner. In summary, these results highlight the need to go beyond monitoring only the cumulative transcript levels for a gene, to separately analysing the expression of its RNA isoforms.

Identification of miRNA biomarkers of pneumonia using RNA-sequencing and bioinformatics analysis

“…POLR2K encodes the smallest subunit of RNA polymerases II, which is the common subunit of three RNA polymerases (36). A previous study speculated that upregulation of POLR2K may facilitate the assembly of polymerase III, thus contributing to cell proliferation and cancer development (36).…”

“…A previous study speculated that upregulation of POLR2K may facilitate the assembly of polymerase III, thus contributing to cell proliferation and cancer development (36). APP encodes a transmembrane precursor protein that is cleaved into peptides by secretases.…”

Alternative polyadenylation: New insights from global analyses

“…These studies were quickly followed by the introduction of high-throughput sequencing-based techniques for global APA analyses that dramatically accelerated the pace of discovery in the field (Jan et al 2010;Mangone et al 2010;Ozsolak et al 2010;Shepard et al 2011). In the past 3 yr alone, the RNA polyadenylation profiles have been characterized for yeast (Ozsolak et al 2010), Caenorhabditis elegans (Jan et al 2010;Mangone et al 2010;Haenni et al 2012), Drosophila (Smibert et al 2012), Arabidopsis (Wu et al 2011;Sherstnev et al 2012), and mammals (Ozsolak et al 2010;Fox-Walsh et al 2011;Fu et al 2011;Shepard et al 2011;Derti et al 2012;Jenal et al 2012;Lin et al 2012). In most of these species, the polyadenylation profiles have been characterized for different tissues and developmental stages.…”

Noncoding RNAs that associate with YB-1 alter proliferation in prostate cancer cells

“…An additional small RNA that is seemingly less abundant is located close to the 3 ′ end. The lack of small RNAs deriving from other regions of RNY3 is reminiscent of other small RNAs that manifest terminal bias, such as tRNA-derived fragments (Lee et al 2009) and snoRNAs-derived RNAs (Taft et al 2009;Lin et al 2012). A more comprehensive analysis of the locations of the small RNAs within shyRNAs indicates that shyRNAs are preferentially processed from their 5 ′ or 3 ′ ends (Fig.…”