A conserved 3'UTR short motif regulates gene expression in vertebrates

Area of Science:

• Molecular Biology
• Genetics
• Developmental Biology

Background:

• The messenger RNA (mRNA) 3' untranslated region (3'UTR) contains regulatory elements crucial for gene expression.
• Upstream sequence elements (USEs) within the 3'UTR play a significant role in regulating gene expression.
• A specific USE in the Drosophila polo gene's 3'UTR influences adult fly phenotypes when altered.

Purpose of the Study:

• To identify and characterize a conserved sequence motif (DplUSE) in vertebrate 3'UTRs.
• To investigate the function of DplUSE in gene expression regulation across species.
• To explore the association of DplUSE with human diseases and developmental processes.

Main Methods:

• Sequence analysis to identify conserved DplUSE motifs in human, zebrafish, and mouse genomes.
• Gene expression assays in human cells and zebrafish embryos to assess DplUSE function.
• RNA-binding protein (RBP) immunoprecipitation and knockdown experiments to identify interacting proteins.
• Analysis of disease-associated genetic variations (SNPs) within DplUSE regions.

Main Results:

• A conserved DplUSE motif was identified in the 3'UTRs of various vertebrate genes.
• DplUSE enhances gene expression in human cells and zebrafish embryos.
• Disruption of DplUSE impairs zebrafish development and is linked to human congenital diseases.
• RBPs including HuR/ELAVL1, hnRNPC, and PTBP1/hnRNPI bind to DplUSE and are essential for its activity.
• PTBP1 regulates alternative polyadenylation of DplUSE-containing genes, while hnRNPC and HuR modulate expression.
• A colon cancer-associated SNP creates an ectopic DplUSE site, increasing gene expression.

Conclusions:

• The DplUSE motif is a conserved regulatory element in vertebrate 3'UTRs controlling gene expression through RBP interactions.
• DplUSE plays a critical role in vertebrate development and its dysregulation is implicated in human congenital diseases.
• This conserved mechanism highlights a fundamental aspect of gene regulation with implications for disease pathogenesis.