Mechanisms of human gamma-globin transcriptional induction by apicidin involves p38 signaling to chromatin.
Histone deacetylase (HDAC) inhibitors are one of promising drugs to induce fetal hemoglobin (HbF) for treatment of sickle cell disease (SCD) and beta-thalassemia. The HDAC inhibitor apicidin was recently reported as a powerful inducer of HbF via a mechanism involving p38 signaling. In this study, we further investigated the signaling effects on the transcriptional activation of gamma-globin gene. First, we compared histone 3 (H3) acetylation patterns of approximately 70kb beta-globin loci in K562 erythroid versus HeLa cells upon apicidin treatment by chromatin immunoprecipitation assays. The results showed that the level of H3 acetylation was globally increased from the LCR to the promoter of gamma-globin gene in K562 cells, but not in non-erythroid, HeLa cells. Inhibition of p38 signaling blocks the effects of apicidin-induced gamma-globin expression and H3 acetylation. In parallel, we assessed the recruitment of transcriptional complex to beta-globin locus following apicidin treatment. The binding of GATA-1, Sp1 and RNA polymerase II (pol II) were observed to increase over several regulatory regions of beta-globin locus. Inhibitor study revealed that p38 pathway was not involved in their recruitments by apicidin. Collectively, our results provide a molecular basis to elucidate the underlying mechanisms involving p38 signaling pathway in the inducement of gamma-globin transcriptional expression by apicidin.
Wei
Gong-Hong
GH
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100005, PR China.
Zhao
Guo-Wei
GW
Song
Wei
W
Hao
De-Long
DL
Lv
Xiang
X
Liu
De-Pei
DP
Liang
Chih-Chuan
CC
D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005914:Globins / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D002843:Chromatin; D010456:Peptides, Cyclic; C102351:apicidin; D005914:Globins; D048051:p38 Mitogen-Activated Protein Kinases