title: Expression of SCL is normal in transfusion-dependent Diamond-Blackfan anemia but other bHLH proteins are deficient.
abstract: Basic helix-loop-helix proteins, which are tissue specific (SCL) or broadly expressed (E proteins), interact positively to regulate erythroid specific genes. Here, expression of SCL and two broadly expressed E proteins, E47 and HEB, was high early in erythroid differentiation and declined during maturation. Stimulation of erythroid progenitors/precursors with stem cell factor (SCF) enhanced SCL and E protein levels, one mechanism by which SCF may increase erythroid proliferation. Interactions between SCL and E proteins are competed by Id2, which binds and sequesters E proteins. Upregulation of Id2, demonstrated here late in erythroid differentiation, may downregulate genes involved in erythroid proliferation/differentiation. We examined expression of bHLH proteins in transfusion-dependent patients with Diamond-Blackfan anemia (DBA) to determine if these interactions are disrupted. In erythroblasts from patients, expression of SCL protein and mRNA was normal and SCL increased in response to SCF. However, E47 and HEB protein levels were significantly decreased. Id2 was strongly expressed in patients. Through reduction of SCL/E protein heterodimer formation, abnormal levels of bHLH transcription factors may affect expression of erythroid specific genes, such as beta globin. Stimulation of Diamond-Blackfan cells with SCF partially compensated for this defect, enhancing expression of E47, HEB, and SCL. SCF may function to increase SCL/E protein heterodimer formation, which may be one of the mechanisms through which SCF stimulates erythroid proliferation/differentiation in DBA.
authors.affiliation: Department of Pediatrics, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA.
authors.forename: M Y
authors.initials: MY
authors.lastname: Zhang
authors.forename: G A
authors.initials: GA
authors.lastname: Clawson
authors.forename: N F
authors.initials: NF
authors.lastname: Olivieri
authors.forename: L L
authors.initials: LL
authors.lastname: Bell
authors.forename: C G
authors.initials: CG
authors.lastname: Begley
authors.forename: B A
authors.initials: BA
authors.lastname: Miller
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins; D001803:Blood Transfusion; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004912:Erythrocytes / Q000378:metabolism*; D005199:Fanconi Anemia / Q000097:blood* / Q000628:therapy; D005786:Gene Expression Regulation; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D011518:Proto-Oncogene Proteins; D019089:Stem Cell Factor / Q000494:pharmacology*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019089:Stem Cell Factor; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C067143:TAL1 protein, human