AIRE recruits multiple transcriptional components to specific genomic regions through tethering to nuclear matrix.
Thymic selection requires that diverse self antigens be presented to developing thymocytes by stromal cells. Consistent with this function, medullary thymic epithelial cells have been shown to express a large number of genes, many of which are tissue restricted. Autoimmune regulator (AIRE) is a nuclear protein, which has recently been identified as a regulator of this process, however, the mechanism by which AIRE functions is not well understood. Here we use a transrepression assay to demonstrate that AIRE interacts with multiple components of the transcription complex including a novel interaction with the UBA domain protein, GBDR1. When AIRE is expressed in cultured human thymic epithelial cells, it tightly associates with nuclear matrix, suggesting that AIRE responsive genes may be localized to specific regions. Using a mathematical approach we have re-analyzed an Affymetrix dataset identifying AIRE responsive genes and show that they tend to localize to specific regions of the genome. Together, these data suggest that AIRE regulates gene expression by recruiting components of the transcription complex to specific regions of the genome via interactions with nuclear matrix.
Tao
Yunxia
Y
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East Ninth Ave. C-238, Denver, CO 80262, USA.
Kupfer
Rene
R
Stewart
Benjamin J
BJ
Williams-Skipp
Cheryll
C
Crowell
Christopher K
CK
Patel
Dhavalkumar D
DD
Sain
Steven
S
Scheinman
Robert I
RI
D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology; D001483:Base Sequence; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002522:Chlorocebus aethiops; D002874:Chromosome Mapping; D003345:Corticosterone; D018076:DNA, Complementary / Q000235:genetics; D020869:Gene Expression Profiling; D005813:Genes, Synthetic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D015530:Nuclear Matrix / Q000502:physiology*; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D017634:Self Tolerance / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D017154:Stromal Cells / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases; D016335:Zinc Fingers / Q000502:physiology; D000096927:AIRE Protein
D001324:Autoantigens; D002352:Carrier Proteins; D003345:Corticosterone; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000096927:AIRE Protein; C412480:UBAC1 protein, human