title: Intermediaries of branched chain amino acid metabolism induce fetal hemoglobin, and repress SOX6 and BCL11A, in definitive erythroid cells.
abstract: High levels of fetal hemoglobin (HbF) can ameliorate human β-globin gene disorders. The short chain fatty acid butyrate is the paradigmatic metabolic intermediary that induces HbF. Inherited disorders of branched-chain amino acid (BCAA) metabolism have been associated with supranormal HbF levels beyond infancy, e.g., propionic acidemia (PA) and methylmalonic acidemia (MMA). We tested intermediaries of BCAA metabolism for their effects on definitive erythropoiesis. Like butyrate, the elevated BCAA intermediaries isovalerate, isobutyrate, and propionate, induce fetal globin gene expression in murine EryD in vitro, are associated with bulk histone H3 hyperacylation, and repress the transcription of key gamma globin regulatory factors, notably BCL11A and SOX6. Metabolic intermediaries that are elevated in Maple Syrup Urine Disease (MSUD) affect none of these processes. Percent HbF and gamma (γ) chain isoforms were also measured in non-anemic, therapeutically optimized subjects with MSUD (Group I, n=6) or with Isovaleric Acidemia (IVA), MMA, or PA (Group II, n=5). Mean HbF was 0.24 ± 0.15% in Group I and 0.87 ± 0.13% in Group II (p=.01); only the Gγ isoform was detected. We conclude that a family of biochemically related intermediaries of branched chain amino acid metabolism induces fetal hemoglobin during definitive erythropoiesis, with mechanisms that mirror those so far identified for butyrate.
authors.affiliation: Division of Hematology, Department of Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Blvd., Bronx, NY 10461, United States.
authors.forename: Shay
authors.initials: S
authors.lastname: Karkashon
authors.affiliation: Division of Hematology, Department of Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Blvd., Bronx, NY 10461, United States.
authors.forename: Radha
authors.initials: R
authors.lastname: Raghupathy
authors.affiliation: Division of Hematology, Department of Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Blvd., Bronx, NY 10461, United States.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Bhatia
authors.affiliation: Division of Hematology, Department of Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Blvd., Bronx, NY 10461, United States.
authors.forename: Amrita
authors.initials: A
authors.lastname: Dutta
authors.affiliation: California Institute of Technology, Beckman Institute, Proteome Exploration Laboratory, 1200 E California Blvd, MC139-74, Pasadena, CA 91125, United States.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hess
authors.affiliation: Division of Genetics and Metabolism, Center for Hospital-based Specialties, Children's National Medical Center, 111 Michigan Ave. N.W., Washington, DC 20010-2970, United States.
authors.forename: Jaimie
authors.initials: J
authors.lastname: Higgs
authors.affiliation: Division of Genetics and Metabolism, Center for Hospital-based Specialties, Children's National Medical Center, 111 Michigan Ave. N.W., Washington, DC 20010-2970, United States.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.affiliation: Division of Hematology, Department of Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Blvd., Bronx, NY 10461, United States. Electronic address: Jane.little@uhhospitals.org.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Little
mesh_terms: D000107:Acetylation; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D041905:Erythroid Cells / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D055755:SOXD Transcription Factors / Q000378:metabolism*; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; C486563:BCL11A protein, human; D002352:Carrier Proteins; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; D055545:gamma-Globins; D005319:Fetal Hemoglobin
keywords: Butyrate; Epigenetic modification; Fetal hemoglobin; Hemoglobinopathies