Intermediaries of branched chain amino acid metabolism induce fetal. hemoglobin, and repress SOX6 and BCL11A, in definitive erythroid cells
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香港中文大學研究人員

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摘要High levels of fetal hemoglobin (HbF) can ameliorate human p-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 (gamma) 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 land 0.87 +/- 0.13% in Group II (p = .01); only the G gamma isoform was detected. We conclude that a family of biochemically related intermediaries of branched chain amino acid metabolism induces fetal hemoglobin during definitive etythropoiesis, with mechanisms that mirror those so far identified for butyrate. (C) 2015 Elsevier Inc. All rights reserved.
著者Karkashon S, Raghupathy R, Bhatia H, Dutta A, Hess S, Higgs J, Tifft CJ, Little JA
期刊名稱Blood Cells, Molecules and Diseases
出版年份2015
月份8
日期1
卷號55
期次2
出版社ACADEMIC PRESS INC ELSEVIER SCIENCE
頁次161 - 167
國際標準期刊號1079-9796
電子國際標準期刊號1096-0961
語言英式英語
關鍵詞Butyrate; Epigenetic modification; Fetal hemoglobin; Hemoglobinopathies
Web of Science 學科類別Hematology

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