title: Duplex stem-loop-containing quadruplex motifs in the human genome: a combined genomic and structural study.
abstract: Duplex stem-loops and four-stranded G-quadruplexes have been implicated in (patho)biological processes. Overlap of stem-loop- and quadruplex-forming sequences could give rise to quadruplex-duplex hybrids (QDH), which combine features of both structural forms and could exhibit unique properties. Here, we present a combined genomic and structural study of stem-loop-containing quadruplex sequences (SLQS) in the human genome. Based on a maximum loop length of 20 nt, our survey identified 80 307 SLQS, embedded within 60 172 unique clusters. Our analysis suggested that these should cover close to half of total SLQS in the entire genome. Among these, 48 508 SLQS were strand-specifically located in genic/promoter regions, with the majority of genes displaying a low number of SLQS. Notably, genes containing abundant SLQS clusters were strongly associated with brain tissues. Enrichment analysis of SLQS-positive genes and mapping of SLQS onto transcriptional/mutagenesis hotspots and cancer-associated genes, provided a statistical framework supporting the biological involvements of SLQS. In vitro formation of diverse QDH by selective SLQS hits were successfully verified by nuclear magnetic resonance spectroscopy. Folding topologies of two SLQS were elucidated in detail. We also demonstrated that sequence changes at mutation/single-nucleotide polymorphism loci could affect the structural conformations adopted by SLQS. Thus, our predicted SLQS offer novel insights into the potential involvement of QDH in diverse (patho)biological processes and could represent novel regulatory signals.
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371, Singapore School of Biological Sciences, Nanyang Technological University, 637551, Singapore.
authors.forename: Kah Wai
authors.initials: KW
authors.lastname: Lim
authors.affiliation: Department of Genome and Gene Expression Data Analysis, Bioinformatics Institute, 138671, Singapore.
authors.forename: Piroon
authors.initials: P
authors.lastname: Jenjaroenpun
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371, Singapore School of Biological Sciences, Nanyang Technological University, 637551, Singapore.
authors.forename: Zhen Jie
authors.initials: ZJ
authors.lastname: Low
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371, Singapore.
authors.forename: Zi Jian
authors.initials: ZJ
authors.lastname: Khong
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371, Singapore.
authors.forename: Yi Siang
authors.initials: YS
authors.lastname: Ng
authors.affiliation: Department of Genome and Gene Expression Data Analysis, Bioinformatics Institute, 138671, Singapore vladimirk@bii.a-star.edu.sg.
authors.forename: Vladimir Andreevich
authors.initials: VA
authors.lastname: Kuznetsov
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371, Singapore phantuan@ntu.edu.sg.
authors.forename: Anh Tuân
authors.initials: AT
authors.lastname: Phan
mesh_terms: D002874:Chromosome Mapping; D054856:G-Quadruplexes; D063990:Gene Ontology; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D015233:Models, Statistical; D009154:Mutation; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism
chemical_list: D012319:RNA Polymerase II