Epigenetic Gene Regulation—Lessons from Globin

Abstract

The globin loci, in particular the β globin locus, have been important models for identifying and understanding the mechanisms of transcriptional regulation in mammals. This is because they are multigenic, tissue specific, developmentally regulated and among the most highly transcribed genes in our genome. In general the chromatin structure of the mammalian β-globin locus reflects the transcriptional state of individual globin genes rather than having a uniform chromatin structure across the locus. A great deal of effort has been devoted to understanding how the β-globin locus control region (LCR) regulates transcription and influences chromatin structure. While studies of transgenes with and without the LCR suggest that the LCR primarily regulates transcription by influencing the overall locus chromatin structure, this does not appear to be the case in the endogenous mouse locus and the LCR appears to have multiple activities in various contexts. Recent studies have led to a new model of how the LCR influences transcriptional regulation and this model, if correct, will have a major influence on understanding transcriptional regulation in mammals. In this model, the LCR augments transcription by influencing the subnuclear localization of the locus in order to maintain the locus in concentrated regions of RNA pol II called transcription factories, in particular, in the transcription factories that contain active pol II with a hyperphosphorylated carboxy terminal domain (CTD). By keeping the locus in association with active transcription factories a large percentage of the time, the LCR appears to mediate the high levels of transcription associated with the β-like globin genes in erythroblasts.