title: How transcriptional and epigenetic programmes are played out on an individual mammalian gene cluster during lineage commitment and differentiation.
abstract: In the post-genomic era, a great deal of work has focused on understanding how DNA sequence is used to programme complex nuclear, cellular and tissue functions throughout differentiation and development. There are many approaches to these issues, but we have concentrated on understanding how a single mammalian gene cluster is activated or silenced as stem cells undergo lineage commitment, differentiation and maturation. In particular we have analysed the alpha globin cluster, which is expressed in a cell-type- and developmental stage-specific manner in the haemopoietic system. Our studies include analysis of the transcriptional programme that accompanies globin gene activation, focusing on the expression of relevant transcription factors and cofactors. Binding of these factors to the chromosomal domain containing the alpha globin cluster has been characterized by ChIP (chromatin immunoprecipitation). In addition, we have monitored the epigenetic modifications (e.g. nuclear position, timing of replication, chromatin modification, DNA methylation) that occur as the genes are activated (in erythroid cells) or silenced (e.g. in granulocytes) as haemopoiesis proceeds. Together, these observations provide a uniquely well-characterized model illustrating the mechanisms that regulate and memorize patterns of mammalian gene expression as stem cells undergo lineage specification, differentiation and terminal maturation.
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. doug.higgs@imm.ox.ac.uk
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.forename: Douglas
authors.initials: D
authors.lastname: Vernimmen
authors.forename: Marco
authors.initials: M
authors.lastname: De Gobbi
authors.forename: Eduardo
authors.initials: E
authors.lastname: Anguita
authors.forename: Jim
authors.initials: J
authors.lastname: Hughes
authors.forename: Veronica
authors.initials: V
authors.lastname: Buckle
authors.forename: Franciso
authors.initials: F
authors.lastname: Iborra
authors.forename: David
authors.initials: D
authors.lastname: Garrick
authors.forename: William G
authors.initials: WG
authors.lastname: Wood
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D044127:Epigenesis, Genetic; D004920:Erythropoiesis / Q000235:genetics; D005809:Genes, Regulator; D005914:Globins / Q000235:genetics; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D005810:Multigene Family; D012319:RNA Polymerase II / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors; D005914:Globins; D012319:RNA Polymerase II