title: AIRE activated tissue specific genes have histone modifications associated with inactive chromatin.
abstract: The Autoimmune Regulator (AIRE) protein is expressed in thymic medullary epithelial cells, where it promotes the ectopic expression of tissue-restricted antigens needed for efficient negative selection of developing thymocytes. Mutations in AIRE cause APECED syndrome, which is characterized by a breakdown of self-tolerance. The molecular mechanism by which AIRE increases the expression of a variety of different genes remains unknown. Here, we studied AIRE-regulated genes using whole genome expression analysis and chromatin immunoprecipitation. We show that AIRE preferentially activates genes that are tissue-specific and characterized by low levels of initial expression in stably transfected HEK293 cell model and mouse thymic medullary epithelial cells. In addition, the AIRE-regulated genes lack active chromatin marks, such as histone H3 trimethylation (H3K4me3) and acetylation (AcH3), on their promoters. We also show that during activation by AIRE, the target genes acquire histone H3 modifications associated with transcription and RNA polymerase II. In conclusion, our data show that AIRE is able to promote ectopic gene expression from chromatin associated with histone modifications characteristic to inactive genes.
authors.affiliation: Department of Molecular Pathology, Institute of General and Molecular Pathology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Tõnis
authors.initials: T
authors.lastname: Org
authors.forename: Ana
authors.initials: A
authors.lastname: Rebane
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
authors.forename: Martti
authors.initials: M
authors.lastname: Laan
authors.forename: Uku
authors.initials: U
authors.lastname: Haljasorg
authors.forename: Reidar
authors.initials: R
authors.lastname: Andreson
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012319:RNA Polymerase II / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000096927:AIRE Protein
chemical_list: D002843:Chromatin; D012319:RNA Polymerase II; D014157:Transcription Factors; D000096927:AIRE Protein