Transcriptional repression and DNA looping associated with a novel regulatory element in the final exon of the lymphotoxin-β gene.
Transcriptional regulation has a critical role in the coordinate and context-specific expression of a cluster of genes encoding members of the tumour necrosis factor (TNF) superfamily found at chromosome 6p21, comprising TNF, LTA (encoding lymphotoxin-α) and LTB (encoding lymphotoxin-β). This is important, as dysregulated expression of these genes is implicated in susceptibility to many autoimmune, inflammatory and infectious diseases. We describe here a novel regulatory element in the fourth exon of LTB, which is highly conserved, localises to the only CpG island in the locus, and is associated with a DNase I hypersensitive site and specific histone modifications. We find evidence of binding by Yin Yang 1 (YY1), cyclic AMP response element (CRE)-binding protein (CREB) and CCCTC-binding factor (CTCF) to this region in Jurkat T cells, which is associated with transcriptional repression on reporter gene analysis. Chromatin conformation capture experiments show evidence of DNA looping, involving interaction of this element with the LTB promoter, LTA promoter and TNF 3' untranslated region (UTR). Small interfering RNA (siRNA) experiments demonstrate a functional role for YY1 and CREB in LTB expression. Our findings provide evidence of additional complexity in the transcriptional regulation of LTB with implications for coordinate expression of genes in this important genomic locus.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
K
K
Wicks
J C
JC
Knight
D000076246:CCCTC-Binding Factor; D017124:Conserved Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D003850:Deoxyribonuclease I / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005786:Gene Expression Regulation; D005809:Genes, Regulator; D006801:Humans; D019169:Jurkat Cells; D053308:Lymphotoxin-beta / Q000235:genetics*; D011401:Promoter Regions, Genetic; D050436:Regulatory Elements, Transcriptional; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D053308:Lymphotoxin-beta; D012097:Repressor Proteins; D050986:YY1 Transcription Factor; D004247:DNA; D003850:Deoxyribonuclease I
Mol Cell Biol. 2009 Apr;29(7):1682-93
19158269
Trends Immunol. 2007 Apr;28(4):169-75
17336158
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16850-5
17940009
J Immunol. 1997 Sep 15;159(6):3034-43
9300729
J Biol Chem. 1998 Aug 14;273(33):21178-86
9694874
J Immunol. 1996 Apr 1;156(7):2465-72
8786306
Mol Cell. 2007 Jan 12;25(1):43-56
17218270
Cell. 1993 Mar 26;72(6):847-56
7916655
Genome Res. 2002 Jun;12(6):996-1006
12045153
Mol Cell Biol. 2006 Nov;26(22):8551-61
16954376
J Immunol. 1991 Sep 1;147(5):1694-700
1715367
J Biol Chem. 2001 Apr 27;276(17):13505-8
11279224
Nat Protoc. 2007;2(7):1722-33
17641637
Science. 1994 Apr 29;264(5159):707-10
8171323
Eur J Immunol. 2006 Aug;36(8):2061-75
16841297
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D91-4
14681366
Annu Rev Immunol. 2005;23:787-819
15771586
Immunol Rev. 2008 Jun;223:202-20
18613838
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W249-52
15215389
J Cell Sci. 2009 May 1;122(Pt 9):1275-84
19386894
Cell. 2009 Jun 26;137(7):1194-211
19563753
Bioinformatics. 2007 Nov 1;23(21):2947-8
17846036
J Pathol. 2003 Jan;199(1):115-21
12474234
Science. 2006 May 26;312(5777):1215-7
16728641
Nat Genet. 2003 Apr;33(4):469-75
12627232
Genome Res. 2005 Aug;15(8):1034-50
16024819
Oncogene. 1995 Jul 6;11(1):97-106
7624137
Oncogene. 1990 Dec;5(12):1743-53
2284094
Mol Cell Biochem. 2000 Sep;212(1-2):5-9
11108130
J Biol. 2003;2(2):13
12760745
Nature. 2007 Aug 2;448(7153):553-60
17603471
Nucleic Acids Res. 1989 Aug 11;17(15):6419
2771659
J Biol Chem. 2003 May 2;278(18):15727-34
12595525
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19296-301
17158804
Mol Cell Biol. 2008 Oct;28(20):6473-82
18662993
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W389-92
15980495
Epigenetics. 2008 May-Jun;3(3):115-8
18458536
Cytokine. 1990 Nov;2(6):389-97
2104232
Mol Cell Biol. 1996 Jun;16(6):2802-13
8649389
J Immunol. 2004 Apr 1;172(7):4332-41
15034048
J Virol. 1995 Jul;69(7):4323-30
7769693
Cell. 2007 May 18;129(4):823-37
17512414
Nucleic Acids Res. 2008 Jan;36(Database issue):D83-7
17981843
Genome Res. 2007 Jun;17(6):877-85
17179217
Mol Cell Biol. 2008 Feb;28(3):1124-35
18039862
Genome Res. 2004 Jun;14(6):1176-87
15140828
Immunol Rev. 2008 Jun;223:186-201
18613837
Nucleic Acids Res. 2008 Sep;36(15):4845-62
18653526
Mol Cell Biol. 2007 Jul;27(14):5147-60
17515611
Cell. 2007 Mar 23;128(6):1231-45
17382889
Science. 2002 Feb 15;295(5558):1306-11
11847345
Mol Cell Biol. 2000 Mar;20(6):2239-47
10688670
J Biol Chem. 2007 Apr 20;282(16):11629-38
17303559
J Interferon Cytokine Res. 2001 Nov;21(11):921-30
11747624