Human Molecular Genetics Advance Access originally published online on September 10, 2009
Human Molecular Genetics 2009 18(24):4699-4710; doi:10.1093/hmg/ddp433
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AIRE activated tissue specific genes have histone modifications associated with inactive chromatin
1 Department of Molecular Pathology, Institute of General and Molecular Pathology and 2 Department of Bioinformatics, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
* To whom correspondence should be addressed at: Molecular Pathology, University of Tartu, Tartu 50411, Estonia. Tel: +372 7374202; Fax: +372 7374207; Email: part.peterson{at}ut.ee
Received July 8, 2009; Accepted September 8, 2009
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.