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To understand how mammalian genes are regulated from their natural chromosomal environment, we have analysed the molecular events occurring throughout a 150 kb chromatin segment containing the alpha globin gene locus as it changes from a poised, silent state in erythroid progenitors, to the fully activated state in late, erythroid cells. Active transcription requires the late recruitment of general transcription factors, mediator and Pol II not only to the promoter but also to its remote regulatory elements. Natural mutants of the alpha cluster show that whereas recruitment of the pre-initiation complex to the upstream elements occurs independently, recruitment to the promoter is largely dependent on the regulatory elements. An improved, quantitative chromosome conformation capture analysis demonstrates that this recruitment is associated with a conformational change, in vivo, apposing the promoter with its remote regulators, consistent with a chromosome looping mechanism. These findings point to a general mechanism by which a gene can be held in a poised state until the appropriate stage for expression, coordinating the level and timing of gene expression during terminal differentiation.

Original publication

DOI

10.1038/sj.emboj.7601654

Type

Journal article

Journal

EMBO J

Publication Date

18/04/2007

Volume

26

Pages

2041 - 2051

Keywords

Animals, Cell Line, Tumor, Chromatin Immunoprecipitation, Chromosomes, Erythroid Cells, Gene Expression Regulation, Globins, Mice, Models, Biological, Models, Molecular, Nucleic Acid Conformation, Regulatory Elements, Transcriptional