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Chromosome looping at the human alpha-globin locus is mediated via the major upstream regulatory element (HS -40).

TitleChromosome looping at the human alpha-globin locus is mediated via the major upstream regulatory element (HS -40).
Publication TypeJournal Article
Year of Publication2009
AuthorsVernimmen D, Marques-Kranc F, Sharpe JA, Sloane-Stanley JA, Wood WG, Wallace HAC, Smith AG, Higgs DR
JournalBlood
Volume114
Issue19
Pagination4253-60
Date Published2009 Nov 5
ISSN1528-0020
Keywordsalpha-Globins, Animals, Base Sequence, Cell Line, Cells, Cultured, Chromosomes, Human, DNA Probes, Erythropoiesis, Female, Gene Regulatory Networks, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Multigene Family, Promoter Regions, Genetic, Regulatory Elements, Transcriptional
Abstract

Previous studies in the mouse have shown that high levels of alpha-globin gene expression in late erythropoiesis depend on long-range, physical interactions between remote upstream regulatory elements and the globin promoters. Using quantitative chromosome conformation capture (q3C), we have now analyzed all interactions between 4 such elements lying 10 to 50 kb upstream of the human alpha cluster and their interactions with the alpha-globin promoter. All of these elements interact with the alpha-globin gene in an erythroid-specific manner. These results were confirmed in a mouse model of human alpha globin expression in which the human cluster replaces the mouse cluster in situ (humanized mouse). We have also shown that expression and all of the long-range interactions depend largely on just one of these elements; removal of the previously characterized major regulatory element (called HS -40) results in loss of all the interactions and alpha-globin expression. Reinsertion of this element at an ectopic location restores both expression and the intralocus interactions. In contrast to other more complex systems involving multiple upstream elements and promoters, analysis of the human alpha-globin cluster during erythropoiesis provides a simple and tractable model to understand the mechanisms underlying long-range gene regulation.

DOI10.1182/blood-2009-03-213439
Alternate JournalBlood
PubMed ID19696202
Grant ListMC_U137961144 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom