The goals of this research are to determine the mechanisms of fetal hemoglobin regulation in the adult, delineate the molecular control of induction of fetal hemoglobin, discover new pharmacologic inducers of Hb F synthesis and clone and characterize trans-acting factors which can activate gamma globin gene transcription.
The specific aims are to: 1) Test the hypothesis that the program of globin gene expression changes from fetal to adult in the course of differentiation of adult erythropoiesis, by analyzing globin gene transcription in single erythroid cells using probes detecting primary globin gene transcripts. 2) Investigate the molecular mechanisms of pharmacologic induction of fetal hemoglobin synthesis. Identify the cis elements which are responsive to butyrate, 5-azacytidine, erythropoietin or hydroxyurea; characterize and clone the trans-acting factors interacting with these elements; and test the role of histone hyperacetylation on the induction of Hb F by butyrate. 3) Investigate the induction of fetal hemoglobin by analogues and derivatives of short chain fatty acids. Develop new assays allowing detection of compounds which induce fetal hemoglobin; determine structural features associated with the property of fetal hemoglobin induction; search for new inducers of fetal hemoglobin synthesis among FDA approved derivatives of short chain fatty acids. 4) Clone transcriptional activators of gamma globin gene expression from human fetal liver or GM979 cell cDNA libraries, a) use PCR based approaches to clone EKLF-type transcriptional factors specifically transactivating the gamma globin gene; b) use modified MEL/beta-YAC cells as target cells to clone gamma gene activators by an immunoselection procedure. 5) Clone the genes responsible for heterocellular hereditary persistence of fetal hemoglobin using a novel functional complementation assay based on transfer of YACs into target cells or transgenic mice carrying the human beta globin locus.
| Hu, Jie Hong; Navas, Patrick; Cao, Hua et al. (2007) Systematic RNAi studies on the role of Sp/KLF factors in globin gene expression and erythroid differentiation. J Mol Biol 366:1064-73 |
| Zhan, Mei; Miller, Chris P; Papayannopoulou, Thalia et al. (2007) MicroRNA expression dynamics during murine and human erythroid differentiation. Exp Hematol 35:1015-25 |
| Navas, Patrick A; Li, Qiliang; Peterson, Kenneth R et al. (2006) Investigations of a human embryonic globin gene silencing element using YAC transgenic mice. Exp Biol Med (Maywood) 231:328-34 |
| Nishino, Tamon; Cao, Hua; Stamatoyannopoulos, George et al. (2006) Effects of human gamma-globin in murine beta-thalassaemia. Br J Haematol 134:100-8 |
| Cao, Hua; Stamatoyannopoulos, George (2006) Histone deacetylase inhibitor FK228 is a potent inducer of human fetal hemoglobin. Am J Hematol 81:981-3 |
| Weinberg, Rona S; Ji, Xinjun; Sutton, Millicent et al. (2005) Butyrate increases the efficiency of translation of gamma-globin mRNA. Blood 105:1807-9 |
| Li, Qiliang; Emery, David W; Han, Hemei et al. (2005) Differences of globin transgene expression in stably transfected cell lines and transgenic mice. Blood 105:3346-52 |
| Song, Chao-Zhong; Gavriilidis, Georgios; Asano, Haruhiko et al. (2005) Functional study of transcription factor KLF11 by targeted gene inactivation. Blood Cells Mol Dis 34:53-9 |
| Mitsuma, Ayako; Asano, Haruhiko; Kinoshita, Tomohiro et al. (2005) Transcriptional regulation of FKLF-2 (KLF13) gene in erythroid cells. Biochim Biophys Acta 1727:125-33 |
| Stamatoyannopoulos, George (2005) Control of globin gene expression during development and erythroid differentiation. Exp Hematol 33:259-71 |
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