Transcriptional impact of Aire varies with cell type.
Aire promotes T cell tolerance by inducing the expression of a broad swath of genes encoding peripheral tissue antigens (PTAs) in medullary epithelial cells (MECs) of the thymus. The exact mechanism used in inducing this ectopic transcription remains obscure. To address this issue, we generated transgenic mice expressing Aire in pancreatic islet beta cells. Gene-expression profiling of such islets revealed that Aire can have a significant impact on transcription in these cells, mainly inducing, but also repressing, transcript levels in a manner comparable with its influence on MECs. The exact transcripts affected differed in MECs and beta cells, with limited overlap between the two sets of Aire-modulated genes. We propose that Aire promotes ectopic gene expression by a generic mechanism that does not depend on any particular characteristics or transcription mechanisms operating in MECs, whereas the cellular environment does govern which genes are actually susceptible to Aire regulation.
Guerau-de-Arellano
Mireia
M
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Mathis
Diane
D
Benoist
Christophe
C
D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D013950:Thymus Gland / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D000096927:AIRE Protein
D007328:Insulin; D014157:Transcription Factors; D000096927:AIRE Protein
J Exp Med. 2007 Oct 29;204(11):2521-8
17908938
Nat Immunol. 2006 Jul;7(7):686-91
16785882
Trends Biochem Sci. 1998 Jul;23(7):242-4
9697411
Diabetes. 1997 May;46(5):887-94
9133560
J Clin Invest. 2008 May;118(5):1712-26
18414681
Proc Natl Acad Sci U S A. 2005 May 17;102(20):7233-8
15883360
Hum Mol Genet. 2002 Feb 15;11(4):397-409
11854172
Nat Immunol. 2007 Feb;8(2):181-90
17195844
Science. 2002 Nov 15;298(5597):1395-401
12376594
J Exp Med. 2004 Oct 18;200(8):1015-26
15492124
Eur J Biochem. 1980 Jun;107(2):303-14
6772444
J Exp Med. 2004 Oct 18;200(8):1039-49
15492126
Cell. 2008 Mar 21;132(6):958-70
18358809
Immunogenetics. 2008 Feb;60(2):105-14
18214467
Annu Rev Immunol. 2006;24:571-606
16551260
Nat Genet. 2006 May;38(5):500-1
16642009
Biostatistics. 2003 Apr;4(2):249-64
12925520
Mol Cell Biol. 2007 Dec;27(24):8815-23
17938200
EMBO Rep. 2008 Apr;9(4):370-6
18292755
J Exp Med. 2005 Jul 4;202(1):33-45
15983066
Hum Mol Genet. 1998;7(10):1547-53
9735375
Curr Opin Immunol. 1989-1990 Apr;2(4):604-6
2517914
Immunity. 2005 Aug;23(2):227-39
16111640
J Immunol. 2005 Feb 15;174(4):1862-70
15699112
Cancer Biol Ther. 2004 Nov;3(11):1045-50
15539936