Poster abstracts

Poster number 74 submitted by Cassia Williams-Rogers

RNA binding proteins, upstream open reading frames, and translational control of human gene expression

Cassia Williams-Rogers (Department of Biological Sciences, Carnegie Mellon University), Matthew Agar-Johnson (Department of Biological Sciences, Carnegie Mellon University), Joel McManus (Department of Biological Sciences, Carnegie Mellon University)

Abstract:
Current research in the area of translational control of gene expression includes examination of the presence of upstream open reading frames (uORFs) that present potential start sites for translation of an mRNA transcript in the 5’transcript leader ahead of the main coding DNA sequence (CDS). While the presence of uORFs is generally thought to suppress translation of downstream genes, the mechanisms by which uORFs impact translation of the CDS are not well defined. Previous work in Drosophila has proposed a translational control mechanism in which the binding of the Sex-lethal RNA binding protein (RBP) downstream of a uORF increases preinitiation complex (PIC) recognition of the uORF start codon, thereby decreasing translation of the CDS (Medenbach, et al., 2011). Our project investigated the extent to which RBPs might regulate uORF usage in human mRNA. We performed computational analyses of human uORF and RBP site conservation and frequency using GENCODE transcript annotations and RBP sites obtained from the Encyclopedia of DNA Elements (ENCODE) project (Van Nostrand, et al., 2020). Genes with highly conserved AUG uORF start codons were enriched for functions and processes related to control of transcription and neurons/neurotransmitter activity. uORFs with start codons conserved among primates were also more likely to have RBP sites downstream than non-conserved uORFs. The RBPs that most often bound downstream of these conserved uORFs include ZNF622, RBM15, CSTF2T, DROSHA, and FTO. Interestingly, separate analysis of genes that have both highly conserved uORFs and downstream RBP sites showed even greater enrichment in RNA polymerase II related activities, serine/threonine kinase activity, and chromatin modification functions. These results provide compelling evidence that RBPs may regulate initiation at some human uORFs. However, further computational and experimental investigation is needed to quantify the potential interactions of the RBPs and uORFs identified here.

Keywords: RNA binding proteins (RBPs), upstream open reading frames (uORFs)