ABSTRACT
Mammalian antibody switch regions (â¼1500 bp) are composed of a series of closely neighboring G4-capable sequences. Whereas numerous structural and genome-wide analyses of roles for minimal G4s in transcriptional regulation have been reported, Long G4-capable regions (LG4s)-like those at antibody switch regions-remain virtually unexplored. Using a novel computational approach we have identified 301 LG4s in the human genome and find LG4s prone to mutation and significantly associated with chromosomal rearrangements in malignancy. Strikingly, 217 LG4s overlap annotated enhancers, and we find the promoters regulated by these enhancers markedly enriched in G4-capable sequences suggesting G4s facilitate promoter-enhancer interactions. Finally, and much to our surprise, we also find single-stranded loops of minimal G4s within individual LG4 loci are frequently highly complementary to one another with 178 LG4 loci averaging >35 internal loop:loop complements of >8 bp. As such, we hypothesized (then experimentally confirmed) that G4 loops within individual LG4 loci directly basepair with one another (similar to characterized stem-loop kissing interactions) forming a hitherto undescribed, higher-order, G4-based secondary structure we term a 'G4 Kiss or G4K'. In conclusion, LG4s adopt novel, higher-order, composite G4 structures directly contributing to the inherent instability, regulatory capacity, and maintenance of these conspicuous genomic regions.
Subject(s)
Enhancer Elements, Genetic , Genome, Human , Guanine , Nucleic Acid Conformation , Base Pairing , G-Quadruplexes , Gene Rearrangement , Genetic Variation , Genomics , Guanine/analysis , Humans , Saccharomyces cerevisiae/genetics , Segmental Duplications, Genomic , Sequence DeletionABSTRACT
To direct online users searching for gynecologic cancer information to accurate content, the Centers for Disease Control and Prevention's (CDC) 'Inside Knowledge: Get the Facts About Gynecologic Cancer' campaign sponsored search engine advertisements in English and Spanish. From June 2012 to August 2013, advertisements appeared when US Google users entered search terms related to gynecologic cancer. Users who clicked on the advertisements were directed to relevant content on the CDC website. Compared with the 3 months before the initiative (March-May 2012), visits to the CDC web pages linked to the advertisements were 26 times higher after the initiative began (June-August 2012) (p<0.01), and 65 times higher when the search engine advertisements were supplemented with promotion on television and additional websites (September 2012-August 2013) (p<0.01). Search engine advertisements can direct users to evidence-based content at a highly teachable moment--when they are seeking relevant information.
