Epigenetics of developmental regulation of mammalian genes

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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.