Submitted September 4, 2008
Accepted April 4, 2009
Short chain fatty acid-mediated effects on erythropoiesis in primary definitive erythroid cells
Himanshu Bhatia, Jennifer L. Hallock, Amrita Dutta, Shay Karkashon, Lauren S. Sterner, Toru Miyazaki, Ann Dean, and Jane A. Little*
Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes & Digestive, & Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
Division of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
* Corresponding author; email: jlittle{at}aecom.yu.edu.
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 
-type globin gene expression in primary erythroid fetal liver cells (eFLCs) after 72 hours in culture, from 1.7±1.2% of total -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 ins/EPO (BIE), at 19.5±8.3% compared with 0.1±0.1% in ins/EPO alone (p<.05). Fetal 
-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 11/15 single eFLCs treated with BIE, but in 0/15 ins/EPO-only treated cells. 65.5±9.9% of butyrate-, and 77.5±4.0% of 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.
