Genetic dissection of the α-globin super-enhancer in vivo.

Hay D., Hughes JR., Babbs C., Davies JOJ., Graham BJ., Hanssen L., Kassouf MT., Marieke Oudelaar AM., Sharpe JA., Suciu MC., Telenius J., Williams R., Rode C., Li P-S., Pennacchio LA., Sloane-Stanley JA., Ayyub H., Butler S., Sauka-Spengler T., Gibbons RJ., Smith AJH., Wood WG., Higgs DR.

Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. These super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. Our study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.

DOI

10.1038/ng.3605

Type

Journal article

Journal

Nat Genet

Publication Date

08/2016

Volume

48

Pages

895 - 903

Keywords

Animals, Chromatin, Embryo, Mammalian, Enhancer Elements, Genetic, Erythroid Cells, Gene Expression Regulation, Mice, Mice, Knockout, Transcription Factors, Transcription, Genetic, alpha-Globins

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