title: Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs.
abstract: Bloom syndrome is a rare autosomal recessive disorder characterized by genetic instability and cancer predisposition, and caused by mutations in the gene encoding the Bloom syndrome, RecQ helicase-like (BLM) protein. To determine whether altered gene expression might be responsible for pathological features of Bloom syndrome, we analyzed mRNA and microRNA (miRNA) expression in fibroblasts from individuals with Bloom syndrome and in BLM-depleted control fibroblasts. We identified mRNA and miRNA expression differences in Bloom syndrome patient and BLM-depleted cells. Differentially expressed mRNAs are connected with cell proliferation, survival, and molecular mechanisms of cancer, and differentially expressed miRNAs target genes involved in cancer and in immune function. These and additional altered functions or pathways may contribute to the proportional dwarfism, elevated cancer risk, immune dysfunction, and other features observed in Bloom syndrome individuals. BLM binds to G-quadruplex (G4) DNA, and G4 motifs were enriched at transcription start sites (TSS) and especially within first introns (false discovery rate ≤ 0.001) of differentially expressed mRNAs in Bloom syndrome compared with normal cells, suggesting that G-quadruplex structures formed at these motifs are physiologic targets for BLM. These results identify a network of mRNAs and miRNAs that may drive the pathogenesis of Bloom syndrome.
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;Department of Medical Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom;
authors: Giang Huong
authors: GH
authors: Nguyen
authors: Departments of Pathology.
authors: Weiliang
authors: W
authors: Tang
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Ana I
authors: AI
authors: Robles
authors: Center for Ecogenetics and Environmental Health, University of Washington, Seattle, WA 98105;
authors: Richard P
authors: RP
authors: Beyer
authors: Immunology and Biochemistry, and.
authors: Lucas T
authors: LT
authors: Gray
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Judith A
authors: JA
authors: Welsh
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Aaron J
authors: AJ
authors: Schetter
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima City 960-1295, Japan; and.
authors: Kensuke
authors: K
authors: Kumamoto
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Xin Wei
authors: XW
authors: Wang
authors: Department of Medical Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom;Department of Cellular and Molecular Medicine, Nordea Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors: Ian D
authors: ID
authors: Hickson
authors: Immunology and Biochemistry, and.
authors: Nancy
authors: N
authors: Maizels
authors: Departments of Pathology,Genome Sciences, University of Washington, Seattle, WA 98195; curtis_harris@nih.gov monnat@u.washington.edu.
authors: Raymond J
authors: RJ
authors: Monnat
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; curtis_harris@nih.gov monnat@u.washington.edu.
authors: Curtis C
authors: CC
authors: Harris
mesh_terms: D001816:Bloom Syndrome / Q000235:genetics*; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D053484:RecQ Helicases / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D004247:DNA; C097151:Bloom syndrome protein; D053484:RecQ Helicases