Histone deacetylase 9 activates gamma-globin gene expression in primary erythroid cells.

ABSTRACT: Strategies to induce fetal hemoglobin (HbF) synthesis for the treatment of ?-hemoglobinopathies probably involve protein modifications by histone deacetylases (HDACs) that mediate ?-globin gene regulation. However, the role of individual HDACs in globin gene expression is not very well understood; thus, the focus of our study was to identify HDACs involved in ?-globin activation. K562 erythroleukemia cells treated with the HbF inducers hemin, trichostatin A, and sodium butyrate had significantly reduced mRNA levels of HDAC9 and its splice variant histone deacetylase-related protein. Subsequently, HDAC9 gene knockdown produced dose-dependent ?-globin gene silencing over an 80-320 nm range. Enforced expression with the pTarget-HDAC9 vector produced a dose-dependent 2.5-fold increase in ?-globin mRNA (p < 0.05). Furthermore, ChIP assays showed HDAC9 binding in vivo in the upstream G?-globin gene promoter region. To determine the physiological relevance of these findings, human primary erythroid progenitors were treated with HDAC9 siRNA; we observed 40 and 60% ?-globin gene silencing in day 11 (early) and day 28 (late) progenitors. Moreover, enforced HDAC9 expression increased ?-globin mRNA levels by 2.5-fold with a simultaneous 7-fold increase in HbF. Collectively, these data support a positive role for HDAC9 in ?-globin gene regulation.

SUBMITTER: Muralidhar SA 

PROVIDER: S-EPMC3023528 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature