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Published August 2015 | public
Journal Article

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.

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

Additional details

Created:
August 22, 2023
Modified:
October 23, 2023