title: The histone demethylase PHF8 is a molecular safeguard of the IFNγ response.
abstract: A precise immune response is essential for cellular homeostasis and animal survival. The paramount importance of its control is reflected by the fact that its non-specific activation leads to inflammatory events that ultimately contribute to the appearance of many chronic diseases. However, the molecular mechanisms preventing non-specific activation and allowing a quick response upon signal activation are not yet fully understood. In this paper we uncover a new function of PHF8 blocking signal independent activation of immune gene promoters. Affinity purifications coupled with mass spectrometry analysis identified SIN3A and HDAC1 corepressors as new PHF8 interacting partners. Further molecular analysis demonstrated that prior to interferon gamma (IFNγ) stimulation, PHF8 is bound to a subset of IFNγ-responsive promoters. Through the association with HDAC1 and SIN3A, PHF8 keeps the promoters in a silent state, maintaining low levels of H4K20me1. Upon IFNγ treatment, PHF8 is phosphorylated by ERK2 and evicted from the promoters, correlating with an increase in H4K20me1 and transcriptional activation. Our data strongly indicate that in addition to its well-characterized function as a coactivator, PHF8 safeguards transcription to allow an accurate immune response.
authors.affiliation: Department of Molecular Genomics, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Asensio-Juan
authors.affiliation: Department of Molecular Genomics, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Fueyo
authors.affiliation: Department of Molecular Genomics, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Stella
authors.initials: S
authors.lastname: Pappa
authors.affiliation: Department of Molecular Genomics, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Simona
authors.initials: S
authors.lastname: Iacobucci
authors.affiliation: Department of Molecular Genomics, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Badosa
authors.affiliation: Vall d'Hebron Institute of Research (VHIR), Passeig de la Vall d'Hebron, 119, E-08035 Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Lois
authors.affiliation: Department of Molecular Genomics, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Balada
authors.affiliation: Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Institut d?Investigació Biomèdica de Bellvitge (IDIBELL), 08907- L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Bosch-Presegué
authors.affiliation: Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Institut d?Investigació Biomèdica de Bellvitge (IDIBELL), 08907- L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Vaquero
authors.affiliation: Department of Cell Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Gutiérrez
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona 08028, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Caelles
authors.affiliation: Department of Cell Biology, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Gallego
authors.affiliation: Vall d'Hebron Institute of Research (VHIR), Passeig de la Vall d'Hebron, 119, E-08035 Barcelona, Spain.|Institut Català per la Recerca i Estudis Avançats (ICREA), Barcelona 08018, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: de la Cruz
authors.affiliation: Department of Molecular Genomics, Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
authors.forename: Marian A
authors.initials: MA
authors.lastname: Martínez-Balbás
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D020868:Gene Silencing; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D014157:Transcription Factors; D007371:Interferon-gamma; D056466:Histone Demethylases; C511934:PHF8 protein, human; D019950:Mitogen-Activated Protein Kinase 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056264:Sin3 Histone Deacetylase and Corepressor Complex