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.