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Intermediaries of branched chain amino acid metabolism induce fetal hemoglobin, and repress SOX6 and BCL11A, in definitive erythroid cells

Karkashon, Shay and Raghupathy, Radha and Bhatia, Himanshu and Dutta, Amrita and Hess, Sonja and Higgs, Jaimie and Tifft, Cynthia J. and Little, Jane A. (2015) Intermediaries of branched chain amino acid metabolism induce fetal hemoglobin, and repress SOX6 and BCL11A, in definitive erythroid cells. Blood Cells, Molecules, and Diseases, 55 (2). pp. 161-167. ISSN 1079-9796. https://resolver.caltech.edu/CaltechAUTHORS:20150807-080019144

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.bcmd.2015.05.006DOIArticle
http://www.sciencedirect.com/science/article/pii/S1079979615000947PublisherArticle
ORCID:
AuthorORCID
Hess, Sonja0000-0002-5904-9816
Additional Information:© 2015 Elsevier Inc. Submitted 21 May 2015; Accepted 25 May 2015; Available online 27 May 2015. Dr. Raghupathy and Shay Karkashon contributed equally to this work
Subject Keywords:Hemoglobinopathies; Fetal hemoglobin; Butyrate; Epigenetic modification
Issue or Number:2
Record Number:CaltechAUTHORS:20150807-080019144
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150807-080019144
Official Citation:Shay Karkashon, Radha Raghupathy, Himanshu Bhatia, Amrita Dutta, Sonja Hess, Jaimie Higgs, Cynthia J. Tifft, Jane A. Little, Intermediaries of branched chain amino acid metabolism induce fetal hemoglobin, and repress SOX6 and BCL11A, in definitive erythroid cells, Blood Cells, Molecules, and Diseases, Volume 55, Issue 2, August 2015, Pages 161-167, ISSN 1079-9796, http://dx.doi.org/10.1016/j.bcmd.2015.05.006. (http://www.sciencedirect.com/science/article/pii/S1079979615000947)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:59299
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:07 Aug 2015 16:09
Last Modified:03 Oct 2019 08:45

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