Pleiotropic role of histone deacetylases in the regulation of human adult erythropoiesis.
Histone acetylation and deacetylation play fundamental roles in transcriptional regulation. We investigated the role of histone deacetylases (HDACs) in human adult haematopoiesis, using the structurally distinct HDAC inhibitors FK228 (depsipeptide) and Trichostatin A. When CD34+ cells were cultured with interleukin (IL)-3 or stem cell factor (SCF) + IL-3, FK228 (0.5 ng/ml) specifically enhanced the generation of immature erythroid cells with a CD36+ glycophorin A (GPA)low phenotype. In semisolid cultures, FK228 promoted the formation of erythroid colonies by CD34+ cells with IL-3 and SCF + IL-3. Furthermore, upon exposure to FK228, CD34+ cell-derived CD36+ GPA- cells were induced to form erythroid colonies with IL-3 alone. Conversely, FK228 inhibited the generation of CD36+ GPAhigh relatively mature erythroid cells from CD34+ cells in the presence of erythropoietin (EPO) and SCF + EPO. FK228 suppressed the EPO-mediated survival of CD36+ GPAlow/- and CD36+ GPAhigh cells and induced their apoptosis. Similar effects were observed for trichostatin A in the generation of erythroid cells in IL-3- and EPO-containing cultures. These data suggest that HDACs negatively regulate the IL-3-mediated growth of early erythroid precursors by suppressing their responsiveness to IL-3, while playing an important role in EPO-mediated differentiation and survival of erythroid precursors. Our data revealed that HDACs have diverse functions in human adult erythropoiesis.
Yamamura
Kentaro
K
Department of Haematology and Oncology, Mie University Graduate School of Medicine, Mie, Japan.
Ohishi
Kohshi
K
Katayama
Naoyuki
N
Yu
Zhaocai
Z
Kato
Keizo
K
Masuya
Masahiro
M
Fujieda
Atsushi
A
Sugimoto
Yuka
Y
Miyata
Eri
E
Shibasaki
Tetsunori
T
Heike
Yuji
Y
Takaue
Yoichi
Y
Shiku
Hiroshi
H
D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D047630:Depsipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004920:Erythropoiesis / Q000187:drug effects / Q000502:physiology*; D004921:Erythropoietin / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D019089:Stem Cell Factor / Q000494:pharmacology
D018952:Antigens, CD34; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007377:Interleukin-3; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D004921:Erythropoietin; C012589:trichostatin A; C087123:romidepsin; D006655:Histone Deacetylases