Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation.

Alternative mRNA processing is a critical mechanism for proteome expansion and gene regulation in higher eukaryotes. The SR family proteins play important roles in splicing regulation. Intriguingly, mammalian genomes encode many poorly characterized SR-like proteins, including subunits of the mRNA 3'-processing factor CFIm, CFIm68 and CFIm59. Here we demonstrate that CFIm functions as an enhancer-dependent activator of mRNA 3' processing. CFIm regulates global alternative polyadenylation (APA) by specifically binding and activating enhancer-containing poly(A) sites (PASs). Importantly, the CFIm activator functions are mediated by the arginine-serine repeat (RS) domains of CFIm68/59, which bind specifically to an RS-like region in the CPSF subunit Fip1, and this interaction is inhibited by CFIm68/59 hyper-phosphorylation. The remarkable functional similarities between CFIm and SR proteins suggest that interactions between RS-like domains in regulatory and core factors may provide a common activation mechanism for mRNA 3' processing, splicing, and potentially other steps in RNA metabolism

Reported microRNA biomarkers in 13 hepatic studies.

<p>Key: Study numbers  =  PMIDs; Green  =  likely; yellow  =  questionable; blue  =  ubiquitous; grey =  unknown; * The same study investigated hepatitis B and muscle injury-induced hepatitis; † Study investigated PBMCs, not just serum or plasma.</p

Flow diagram for proposed future microRNA biomarker studies.

<p>Flow diagram for proposed future microRNA biomarker studies.</p

Six microRNAs have been identified as biomarkers for 9 or more diseases.

<p>Green arrows  =  higher in disease; red arrows  =  lower in disease; grey arrows  =  up or down in disease depending on the study.</p

microRNA expression patterns across 18 cell types.

<p>These 157 microRNAs have variable expression patterns across the 18 cell types. Cells clustering cleanly separates hematopoetic (H) and nonhematopoetic (NH) cell types.</p

Studies of non-neoplastic serum, plasma or PBMC microRNAs biomarkers.

<p>*Citations for these studies are in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089565#pone.0089565.s010" target="_blank">Table S6</a>.</p