title: Genetic dissection of the α-globin super-enhancer in vivo.
abstract: 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.
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hay
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Jim R
authors.initials: JR
authors.lastname: Hughes
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Babbs
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: James O J
authors.initials: JOJ
authors.lastname: Davies
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Bryony J
authors.initials: BJ
authors.lastname: Graham
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Lars
authors.initials: L
authors.lastname: Hanssen
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Mira T
authors.initials: MT
authors.lastname: Kassouf
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: A Marieke
authors.initials: AM
authors.lastname: Marieke Oudelaar
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Sharpe
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Suciu
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Jelena
authors.initials: J
authors.lastname: Telenius
authors.affiliation: Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Williams
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Rode
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Pik-Shan
authors.initials: PS
authors.lastname: Li
authors.affiliation: Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California.|MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Sloane-Stanley
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Ayyub
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Butler
authors.affiliation: Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Sauka-Spengler
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gibbons
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Andrew J H
authors.initials: AJH
authors.lastname: Smith
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Wood
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D041905:Erythroid Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D055542:alpha-Globins / Q000235:genetics*
chemical_list: D002843:Chromatin; D014157:Transcription Factors; D055542:alpha-Globins