title: Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor.
abstract: The identification of transcriptional regulatory networks, which control tissue-specific development and function, is of central importance to the understanding of lymphocyte biology. To decipher transcriptional networks in T-cell development and differentiation we developed a browsable expression atlas and applied a novel quantitative method to define gene sets most specific to each of the represented cell subsets and tissues. Using this system, body atlas size datasets can be used to examine gene enrichment profiles from a cell/tissue perspective rather than gene perspective, thereby identifying highly enriched genes within a cell type, which are often key to cellular differentiation and function. A systems analysis of transcriptional regulators within T cells during different phases of development and differentiation resulted in the identification of known key regulators and uncharacterized coexpressed regulators. ZBTB25, a BTB-POZ family transcription factor, was identified as a highly T cell-enriched transcription factor. We provide evidence that ZBTB25 functions as a negative regulator of nuclear factor of activated T cells (NF-AT) activation, such that RNA interference mediated knockdown resulted in enhanced activation of target genes. Together, these findings suggest a novel mechanism for NF-AT mediated gene expression and the compendium of expression data provides a quantitative platform to drive exploration of gene expression across a wide range of cell/tissue types.
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA.
authors.forename: Yair
authors.initials: Y
authors.lastname: Benita
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Cao
authors.forename: Cosmas
authors.initials: C
authors.lastname: Giallourakis
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Agnès
authors.initials: A
authors.lastname: Gardet
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005796:Genes; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics; D050778:NFATC Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; C068804:ZBTB25 protein, human
references.citation: Nat Immunol. 2003 Jun;4(6):533-9
references.pmid: 12717433
references.citation: Development. 1999 Jun;126(14):3131-48
references.pmid: 10375504
references.citation: Biochem Biophys Res Commun. 2002 Feb 15;291(1):101-10
references.pmid: 11829468
references.citation: J Immunol. 2007 Jul 1;179(1):421-38
references.pmid: 17579063
references.citation: Nat Genet. 1996 Dec;14(4):457-60
references.pmid: 8944026
references.citation: J Exp Med. 2007 Nov 26;204(12):3003-15
references.pmid: 17998389
references.citation: Nat Biotechnol. 1996 Dec;14(13):1675-80
references.pmid: 9634850
references.citation: J Biol Chem. 2003 Jun 20;278(25):22928-38
references.pmid: 12663651
references.citation: Leukemia. 2008 Dec;22(12):2201-7
references.pmid: 18769450
references.citation: Immunobiology. 1995 Jul;193(2-4):281-7
references.pmid: 8530156
references.citation: Nuklearmedizin. 2004 Oct;43(5):171-6
references.pmid: 15480506
references.citation: Science. 2003 Feb 14;299(5609):1057-61
references.pmid: 12522256
references.citation: Nature. 2005 Feb 24;433(7028):826-33
references.pmid: 15729333
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: Bioinformatics. 2005 May 1;21(9):2067-75
references.pmid: 15657102
references.citation: J Biol Chem. 1998 Jun 26;273(26):16551-4
references.pmid: 9632725
references.citation: Mol Cell Biol. 1998 Dec;18(12):6939-50
references.pmid: 9819382
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D747-50
references.pmid: 17132828
references.citation: Nat Rev Immunol. 2008 Jan;8(1):9-21
references.pmid: 18097446
references.citation: Nat Rev Immunol. 2008 Oct;8(10):788-801
references.pmid: 18802443
references.citation: J Biol Chem. 2009 Mar 13;284(11):6683-9
references.pmid: 19141611
references.citation: Life Sci. 2009 Jun 19;84(25-26):894-902
references.pmid: 19376136
references.citation: Nat Immunol. 2005 Apr;6(4):373-81
references.pmid: 15750595
references.citation: Blood. 2006 Sep 15;108(6):1991-8
references.pmid: 16728701
references.citation: Nature. 2004 Jun 3;429(6991):566-71
references.pmid: 15152264
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: Eur J Immunol. 1997 May;27(5):1292-5
references.pmid: 9174623
references.citation: Nat Rev Immunol. 2009 Feb;9(2):125-35
references.pmid: 19151747
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14392-7
references.pmid: 12381789
references.citation: Int J Cancer. 1995 May 29;61(5):706-15
references.pmid: 7768645
references.citation: Cell Stem Cell. 2007 Nov;1(5):578-91
references.pmid: 18371395
references.citation: Cell. 1997 May 16;89(4):587-96
references.pmid: 9160750
references.citation: Neurosci Res. 1999 Dec 30;35(4):281-90
references.pmid: 10617319
references.citation: Dev Cell. 2005 Feb;8(2):153-66
references.pmid: 15691758
references.citation: Dev Biol. 2009 Jan 15;325(2):444-67
references.pmid: 19013443
references.citation: Nat Immunol. 2005 May;6(5):472-80
references.pmid: 15834410
references.citation: Nat Genet. 2000 Apr;24(4):372-6
references.pmid: 10742100
references.citation: Science. 1999 Oct 15;286(5439):531-7
references.pmid: 10521349
references.citation: Blood. 2007 Oct 1;110(7):2537-44
references.pmid: 17615291
references.citation: Cell. 2000 Mar 17;100(6):655-69
references.pmid: 10761931
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Cell. 2002 Nov 27;111(5):621-33
references.pmid: 12464175