title: Fetal globin gene repressors as drug targets for molecular therapies to treat the β-globinopathies.
abstract: The human β-globin locus is comprised of embryonic, fetal, and adult globin genes that are expressed in a developmental stage-specific manner. Mutations in the globin locus give rise to the β-globinopathies, β-thalassemia and sickle cell disease, which begin to manifest symptoms around the time of birth. Although the fetal globin genes are autonomously silenced in adult-stage erythroid cells, mutations lying both within and outside the locus lead to natural variations in the level of fetal globin gene expression, and some of these significantly ameliorate the clinical symptoms of the β-globinopathies. Multiple reports have now identified several transcription factors that are involved in fetal globin gene repression in definitive (adult)-stage erythroid cells (the TR2/TR4 heterodimer, MYB, KLFs, BCL11A, and SOX6). To carry out their repression functions, chromatin-modifying enzymes (such as DNA methyltransferase, histone deacetylases, and lysine-specific histone demethylase 1) are additionally involved as a consequence of forming large macromolecular complexes with the DNA-binding subunits of these cellular machines. This review focuses on the molecular mechanisms underlying fetal globin gene silencing and possible near-future molecularly targeted therapies for treating the β-globinopathies.
authors.affiliation: Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan Tohoku Medical Megabank, Tohoku University, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA engel@umich.edu.
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
mesh_terms: D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006453:Hemoglobinopathies / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; D014157:Transcription Factors; D005319:Fetal Hemoglobin