Characterization of long G4-rich enhancer-associated genomic regions engaging in a novel loop:loop 'G4 Kissing' interaction.

Published

Journal Article

Mammalian antibody switch regions (∼1500 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.

Full Text

Duke Authors

Cited Authors

  • Williams, JD; Houserova, D; Johnson, BR; Dyniewski, B; Berroyer, A; French, H; Barchie, AA; Bilbrey, DD; Demeis, JD; Ghee, KR; Hughes, AG; Kreitz, NW; McInnis, CH; Pudner, SC; Reeves, MN; Stahly, AN; Turcu, A; Watters, BC; Daly, GT; Langley, RJ; Gillespie, MN; Prakash, A; Larson, ED; Kasukurthi, MV; Huang, J; Jinks-Robertson, S; Borchert, GM

Published Date

  • June 19, 2020

Published In

Volume / Issue

  • 48 / 11

Start / End Page

  • 5907 - 5925

PubMed ID

  • 32383760

Pubmed Central ID

  • 32383760

Electronic International Standard Serial Number (EISSN)

  • 1362-4962

Digital Object Identifier (DOI)

  • 10.1093/nar/gkaa357

Language

  • eng

Conference Location

  • England