title: The immediate early gene product EGR1 and polycomb group proteins interact in epigenetic programming during chondrogenesis.
abstract: Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3) blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis.
authors.affiliation: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Spaapen
authors.forename: Guus G H
authors.initials: GG
authors.lastname: van den Akker
authors.forename: Marjolein M J
authors.initials: MM
authors.lastname: Caron
authors.forename: Peggy
authors.initials: P
authors.lastname: Prickaerts
authors.forename: Celine
authors.initials: C
authors.lastname: Rofel
authors.forename: Vivian E H
authors.initials: VE
authors.lastname: Dahlmans
authors.forename: Don A M
authors.initials: DA
authors.lastname: Surtel
authors.forename: Yvette
authors.initials: Y
authors.lastname: Paulis
authors.forename: Finja
authors.initials: F
authors.lastname: Schweizer
authors.forename: Tim J M
authors.initials: TJ
authors.lastname: Welting
authors.forename: Lars M
authors.initials: LM
authors.lastname: Eijssen
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Voncken
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D020219:Chondrogenesis / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks / Q000235:genetics; D017781:Genes, Immediate-Early / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D051379:Mice; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D051766:Early Growth Response Protein 1; D006657:Histones; D063146:Polycomb-Group Proteins; D055758:SOX9 Transcription Factor