title: Short-chain fatty acid-mediated effects on erythropoiesis in primary definitive erythroid cells.
abstract: Short-chain fatty acids (SCFAs; butyrate and propionate) up-regulate embryonic/fetal globin gene expression through unclear mechanisms. In a murine model of definitive erythropoiesis, SCFAs increased embryonic beta-type globin gene expression in primary erythroid fetal liver cells (eFLCs) after 72 hours in culture, from 1.7% (+/- 1.2%) of total beta-globin gene expression at day 0 to 4.9% (+/- 2.2%) in propionate and 5.4% (+/- 3.4%) in butyrate; this effect was greater in butyrate plus insulin/erythropoietin (BIE), at 19.5% (+/- 8.3%) compared with 0.1% (+/- 0.1%) in ins/EPO alone (P < .05). Fetal gamma-globin gene expression was increased in human transgene-containing eFLCs, to 35.9% (+/- 7.0%) in BIE compared with 4.4% (+/- 4.2%) in ins/EPO only (P < .05). Embryonic globin gene expression was detectable in 11 of 15 single eFLCs treated with BIE, but in0 of 15 ins/EPO-only treated cells. Butyrate-treated [65.5% (+/- 9.9%)] and 77.5% (+/- 4.0%) propionate-treated eFLCs were highly differentiated in culture, compared with 21.5% (+/- 3.5%) in ins/EPO (P < .005). Importantly, signaling intermediaries, previously implicated in induced embryonic/fetal globin gene expression (STAT5, p42/44, and p38), were not differentially activated by SCFAs in eFLCs; but increased bulk histone (H3) acetylation was seen in SCFA-treated eFLCs. SCFAs induce embryonic globin gene expression in eFLCS, which are a useful short-term and physiologic primary cell model of embryonic/fetal globin gene induction during definitive erythropoiesis.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Bhatia
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hallock
authors.forename: Amrita
authors.initials: A
authors.lastname: Dutta
authors.forename: Shay
authors.initials: S
authors.lastname: Karkashon
authors.forename: Lauren S
authors.initials: LS
authors.lastname: Sterner
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Ann
authors.initials: A
authors.lastname: Dean
authors.forename: Jane A
authors.initials: JA
authors.lastname: Little
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects*; D005333:Fetus / Q000166:cytology / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005865:Gestational Age; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology; D008297:Male; D043586:Methylmalonyl-CoA Decarboxylase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D056693:Propionic Acidemia; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D055544:beta-Globins / Q000096:biosynthesis* / Q000235:genetics; D055545:gamma-Globins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002087:Butyrates; D011422:Propionates; D011993:Recombinant Fusion Proteins; D055544:beta-Globins; D055545:gamma-Globins; D043586:Methylmalonyl-CoA Decarboxylase