title: Effect of ATRX and G-Quadruplex Formation by the VNTR Sequence on α-Globin Gene Expression.
abstract: ATR-X (α-thalassemia/mental retardation X-linked) syndrome is caused by mutations in chromatin remodeler ATRX. ATRX can bind the variable number of tandem repeats (VNTR) sequence in the promoter region of the α-globin gene cluster. The VNTR sequence, which contains the potential G-quadruplex-forming sequence CGC(GGGGCGGGG)n , is involved in the downregulation of α-globin expression. We investigated G-quadruplex and i-motif formation in single-stranded DNA and long double-stranded DNA. The promoter region without the VNTR sequence showed approximately twofold higher luciferase activity than the promoter region harboring the VNTR sequence. G-quadruplex stabilizers hemin and TMPyP4 reduced the luciferase activity, whereas expression of ATRX led to a recovery in reporter activity. Our results demonstrate that stable G-quadruplex formation by the VNTR sequence downregulates the expression of α-globin genes and that ATRX might bind to and resolve the G-quadruplex.
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan.
authors.forename: Junetha
authors.initials: J
authors.lastname: Syed
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan.
authors.forename: Sefan
authors.initials: S
authors.lastname: Asamitsu
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.affiliation: Department of Medical Ethics and Medical Genetics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Wada
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan. hs@kuchem.kyoto-u.ac.jp.|Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, 606-8501, Japan. hs@kuchem.kyoto-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D001483:Base Sequence; D002942:Circular Dichroism; D004265:DNA Helicases / Q000378:metabolism*; D015536:Down-Regulation; D054856:G-Quadruplexes; D005786:Gene Expression Regulation / Q000235:genetics*; D017930:Genes, Reporter; D006427:Hemin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D018598:Minisatellite Repeats / Q000235:genetics*; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055542:alpha-Globins / Q000235:genetics* / Q000378:metabolism
chemical_list: D011166:Porphyrins; D055542:alpha-Globins; C021096:tetra(4-N-methylpyridyl)porphine; D006427:Hemin; D004265:DNA Helicases
keywords: ATR-X syndrome; ATRX; G-quadruplex; VNTR sequence; alpha-globin gene