title: DNA sequences regulating human globin gene transcription in nondeletional hereditary persistence of fetal hemoglobin.
abstract: Strong genetic evidence supports the idea that point mutations in the promoter of gamma-globin genes overexpressed in adult age [hereditary persistence of fetal hemoglobin (HPFH)] are responsible for the observed phenotype. DNA binding sites for ubiquitous and/or erythroid specific nuclear proteins correlate in location with the positions of point mutations responsible for HPFH. The analysis of the effects of one of these mutations (-175 T greater than C) on in vitro binding of nuclear proteins and on the activity of the mutated promoter in transfection assays indicates that altered binding of the erythroid-specific protein NFE-1 may be responsible for increased activity of the mutated promoter. Other HPFH mutations close to the distal CCAAT box (-117 G greater than A and 13 nucleotide deletions, -114 to -102) have complex effects on in vitro binding of nuclear proteins; their only common effect is the loss of binding of the erythroid-specific factor NFE3. If mechanisms generating the HPFH phenotype are homogeneous, NFE3 might be a negatively acting factor; alternatively, heterogeneous mechanisms might operate and HPFH might additionally be related to loss of binding to the distal CCAAT box region of either NFE1 (-117 HPFH) or of the ubiquitous CCAAT displacement protein-CDP (13 nucleotides deletion). Finally, it is also proposed that increased activity of the HPFH promoters may secondarily cause decreased expression of the delta- and beta-globin genes in cis possibly by competition between gamma- and beta-globin promoters for interaction with common regulatory elements.
authors: Dipartimento di Genetica e di Biologia dei Microrganismi Università degli Studi di Milano, Italy.
authors: S
authors: S
authors: Ottolenghi
authors: R
authors: R
authors: Mantovani
authors: S
authors: S
authors: Nicolis
authors: A
authors: A
authors: Ronchi
authors: B
authors: B
authors: Giglioni
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005006:Ethnicity; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D005796:Genes; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D006453:Hemoglobinopathies / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D005914:Globins; D004247:DNA; D005319:Fetal Hemoglobin