title: MK3 controls Polycomb target gene expression via negative feedback on ERK.
abstract: BACKGROUND
  Gene-environment interactions are mediated by epigenetic mechanisms. Polycomb Group proteins constitute part of an epigenetic cellular transcriptional memory system that is subject to dynamic modulation during differentiation. Molecular insight in processes that control dynamic chromatin association and dissociation of Polycomb repressive complexes during and beyond development is limited. We recently showed that MK3 interacts with Polycomb repressive complex 1 (PRC1). The functional relevance of this interaction, however, remained poorly understood. MK3 is activated downstream of mitogen- and stress-activated protein kinases (M/SAPKs), all of which fulfill crucial roles during development. We here use activation of the immediate-early response gene ATF3, a bona fide PRC1 target gene, as a model to study how MK3 and its effector kinases MAPK/ERK and SAPK/P38 are involved in regulation of PRC1-dependent ATF3 transcription.
  
  
  RESULTS
  Our current data show that mitogenic signaling through ERK, P38 and MK3 regulates ATF3 expression by PRC1/chromatin dissociation and epigenetic modulation. Mitogenic stimulation results in transient P38-dependent H3S28 phosphorylation and ERK-driven PRC1/chromatin dissociation at PRC1 targets. H3S28 phosphorylation by itself appears not sufficient to induce PRC1/chromatin dissociation, nor ATF3 transcription, as inhibition of MEK/ERK signaling blocks BMI1/chromatin dissociation and ATF3 expression, despite induced H3S28 phosphorylation. In addition, we establish that concomitant loss of local H3K27me3 promoter marking is not required for ATF3 activation. We identify pERK as a novel signaling-induced binding partner of PRC1, and provide evidence that MK3 controls ATF3 expression in cultured cells via negative regulatory feedback on M/SAPKs. Dramatically increased ectopic wing vein formation in the absence of Drosophila MK in a Drosophila ERK gain-of-function wing vein patterning model, supports the existence of MK-mediated negative feedback regulation on pERK.
  
  
  CONCLUSIONS
  We here identify and characterize important actors in a PRC1-dependent epigenetic signal/response mechanism, some of which appear to be nonspecific global responses, whereas others provide modular specificity. Our findings provide novel insight into a Polycomb-mediated epigenetic mechanism that dynamically controls gene transcription and support a direct link between PRC1 and cellular responses to changes in the microenvironment.
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.|Laboratoire de Biologie du Développement UMR 7622, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie-Paris 6, 9 Quai Saint-Bernard, 75005, Paris, France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Prickaerts
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
authors.forename: Hanneke Ec
authors.initials: HE
authors.lastname: Niessen
authors.affiliation: Laboratoire de Biologie du Développement UMR 7622, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie-Paris 6, 9 Quai Saint-Bernard, 75005, Paris, France.
authors.forename: Emmanuèle
authors.initials: E
authors.lastname: Mouchel-Vielh
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
authors.forename: Vivian Eh
authors.initials: VE
authors.lastname: Dahlmans
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
authors.forename: Guus Gh
authors.initials: GG
authors.lastname: van den Akker
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Geijselaers
authors.affiliation: BiGCaT Bioinformatics, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
authors.forename: Michiel E
authors.initials: ME
authors.lastname: Adriaens
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Spaapen
authors.affiliation: Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152, Martinsried, Germany.
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Rapp
authors.affiliation: Laboratoire de Biologie du Développement UMR 7622, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie-Paris 6, 9 Quai Saint-Bernard, 75005, Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Peronnet
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Voncken