title: Gene silencing quantitatively controls the function of a developmental trans-activator.
abstract: How a single cell gives rise to progeny with differing fates remains poorly understood. We examined cells lacking methyl CpG binding domain protein-2 (MBD2), a molecule that has been proposed to link DNA methylation to silent chromatin. Helper T cells from Mbd2(-/-) mice exhibit disordered differentiation. IL-4, the signature of a restricted set of progeny, is expressed ectopically in Mbd2(-/-) parent and daughter cells. Loss of MBD2-mediated silencing renders the normally essential activator, Gata-3, dispensable for IL-4 induction. Gata-3 and MBD2 act in competition, wherein each factor independently, and quantitatively, regulates the binary choice of whether heritable IL-4 expression is established. Gata-3 functions, in part, to displace MBD2 from methylated DNA. These results suggest that activating and silencing signals integrate to provide spatially and temporally restricted patterns of gene activity.
authors.affiliation: Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Hutchins
authors.forename: Alan C
authors.initials: AC
authors.lastname: Mullen
authors.forename: Hubert W
authors.initials: HW
authors.lastname: Lee
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Sykes
authors.forename: Frances A
authors.initials: FA
authors.lastname: High
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hendrich
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bird
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C115368:MBD2 protein; D015534:Trans-Activators; D015847:Interleukin-4