We determined epigenetic modification signatures and chromatin structure at high resolution across 300 Kb of human chromosome 11 including the beta-globin locus. Mono-methylated H3 K4, H3 K9 and H3 K36 were broadly distributed, with K4 mono-methylation, in particular, marking the LCR enhancer region. Di- and tri-methylated forms of H3 appeared at highly transcribed globin genes at the expense of the mono-methyl mark, consistent with a transcription coupled mechanism of enzymatic conversion. However, H3 K36 tri-methylation was strongly detected in transcribed coding as well as non-coding regions of the locus leading us to propose that in mammals H3 K36 tri-methylation is a stable mark on sequences transcribed at any level. Interestingly, most epigenetic and chromatin structural features did not undergo transitions at the presumed borders of the globin domain where the insulator factor CTCF interacts, raising questions about the function of the borders. At this juncture, it seems that new models of enhancer-insulator antagonism are needed in this evolving field. We are extending these studies to include normal erythroid precursor cells by following locus wide epigenetic modification during differentiation.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2007
Total Cost
$335,949
Indirect Cost
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State
Country
United States
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Sripichai, Orapan; Kiefer, Christine M; Bhanu, Natarajan V et al. (2009) Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming. Blood 114:2299-306
Kiefer, Christine M; Hou, Chunhui; Little, Jane A et al. (2008) Epigenetics of beta-globin gene regulation. Mutat Res :
Kim, AeRi; Kiefer, Christine M; Dean, Ann (2007) Distinctive signatures of histone methylation in transcribed coding and noncoding human beta-globin sequences. Mol Cell Biol 27:1271-9
Kim, Aeri; Zhao, Hui; Ifrim, Ina et al. (2007) Beta-globin intergenic transcription and histone acetylation dependent on an enhancer. Mol Cell Biol 27:2980-6