Butyrate increases the efficiency of translation of gamma-globin mRNA.
Fetal hemoglobin (Hb F) levels increase in most patients with sickle cell disease following intermittent butyrate therapy. Although the full effects of butyrate on Hb F levels usually require multiple treatment cycles, in some patients a peak level is achieved after a few days of butyrate therapy. Our investigation of the mechanism(s) responsible for this rapid induction of Hb F by butyrate showed that reticulocyte gamma-globin chain synthesis markedly increased within 24 hours of butyrate exposure, without concomitant changes in reticulocyte gamma-globin mRNA levels. This suggests that butyrate might induce Hb F by increasing the efficiency of translation of gamma-globin mRNA. This hypothesis was confirmed by ribosome loading studies that demonstrated enrichment of the polysomal fraction of reticulocytes with gamma-globin mRNA following butyrate exposure. Thus, the induction of Hb F by butyrate may be mediated by translational effects in addition to its well-known effects on transcription of the gamma-globin genes.
Department of Medicine, Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY, USA. rweinberg@nybloodcenter.org
Rona S
RS
Weinberg
Xinjun
X
Ji
Millicent
M
Sutton
Susan
S
Perrine
Yelena
Y
Galperin
Qiliang
Q
Li
Stephen A
SA
Liebhaber
George
G
Stamatoyannopoulos
George F
GF
Atweh
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use; D005319:Fetal Hemoglobin / Q000096:biosynthesis / Q000235:genetics; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000097:blood; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism
D002087:Butyrates; D012333:RNA, Messenger; D005914:Globins; D005319:Fetal Hemoglobin; D001120:Arginine; C033018:arginine butyrate