title: Transcriptional and epigenetic basis for restoration of G6PD enzymatic activity in human G6PD-deficient cells.
abstract: HDAC inhibitors (HDACi) increase transcription of some genes through histone hyperacetylation. To test the hypothesis that HDACi-mediated enhanced transcription might be of therapeutic value for inherited enzyme deficiency disorders, we focused on the glycolytic and pentose phosphate pathways (GPPPs). We show that among the 16 genes of the GPPPs, HDACi selectively enhance transcription of glucose 6-phosphate dehydrogenase (G6PD). This requires enhanced recruitment of the generic transcription factor Sp1, with commensurate recruitment of histone acetyltransferases and deacetylases, increased histone acetylation, and polymerase II recruitment to G6PD. These G6PD-selective transcriptional and epigenetic events result in increased G6PD transcription and ultimately restored enzymatic activity in B cells and erythroid precursor cells from patients with G6PD deficiency, a disorder associated with acute or chronic hemolytic anemia. Therefore, restoration of enzymatic activity in G6PD-deficient nucleated cells is feasible through modulation of G6PD transcription. Our findings also suggest that clinical consequences of pathogenic missense mutations in proteins with enzymatic function can be overcome in some cases by enhancement of the transcriptional output of the affected gene.
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Makarona
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Valentina S
authors.initials: VS
authors.lastname: Caputo
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Joana R
authors.initials: JR
authors.lastname: Costa
authors.affiliation: Department of Paediatrics, Children's Hospital and Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and John Radcliffe Hospital, Headington, Oxford, United Kingdom;
authors.forename: Binbin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: O'Connor
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Deena
authors.initials: D
authors.lastname: Iskander
authors.affiliation: Blood Sciences Service, Hammersmith Hospital, Imperial College Healthcare National Health Service Trust, London, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Roper
authors.affiliation: Blood Sciences Service, Hammersmith Hospital, Imperial College Healthcare National Health Service Trust, London, United Kingdom;
authors.forename: Lynn
authors.initials: L
authors.lastname: Robertson
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Neha
authors.initials: N
authors.lastname: Bhatnagar
authors.affiliation: Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece;
authors.forename: Evangelos
authors.initials: E
authors.lastname: Terpos
authors.affiliation: Department of Biological Chemistry, School of Medicine, Aristoteleion University of Thessaloniki, Thessaloniki, Greece;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Georgiou
authors.affiliation: American Hellenic Educational Progressive Association Hospital, Aristoteleion University Medical School, Thessaloniki, Greece; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Papaioannou
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: D Mark
authors.initials: DM
authors.lastname: Layton
authors.affiliation: Istituto Toscano Tumori, Firenze, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Luzzatto
authors.affiliation: Department of Paediatrics, Children's Hospital and Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and John Radcliffe Hospital, Headington, Oxford, United Kingdom;
authors.forename: Irene
authors.initials: I
authors.lastname: Roberts
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Anastasios
authors.initials: A
authors.lastname: Karadimitris
mesh_terms: D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005954:Glucosephosphate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000201:enzymology / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D056572:Histone Deacetylase Inhibitors; D005954:Glucosephosphate Dehydrogenase