LncRNA DQ786243 affects Treg related CREB and Foxp3 expression in Crohn’s disease
Tóm tắt
Long non-coding RNAs (lncRNAs) have different functions in cells. They work as signals, decoys, guides, and scaffolds. Altered lncRNA levels can affect the expression of gene products. There are seldom studies on the role of lncRNAs in inflammatory bowel disease (IBD). Quantitative RT-PCR showed that DQ786243 was significantly overexpressed in clinical active CD patients compared with clinical inactive CD patients (P = 0.0118) or healthy controls (P = 0.002). CREB was also more highly expressed in active CD than in inactive CD (P = 0.0034) or controls (P = 0.0241). Foxp3 was interestingly lower in inactive CD than in active CD (P = 0.0317) or controls (P = 0.0103), but there were no apparent differences between active CD and controls. CRP was well correlated with DQ786243 (r = 0.489, P = 0.034), CREB (r = 0.500, P = 0.029) and Foxp3 (r = 0.546, P = 0.016). At 48 hours after DQ786243 transfection, qRT-PCR showed both CREB (P = 0.017) and Foxp3 (P = 0.046) had an increased mRNA expression in Jurkat cells. Western blot showed the same pattern. After DQ786243 transfection, CREB phosphorylation ratio (p-CREB/t-CREB) was increased (P = 0.0043). DQ786243 can be related with severity of CD. It can affect the expression of CREB and Foxp3 through which regulates the function of Treg. CREB itself seems not the mediator of DQ786243 to up-regulate Foxp3. The phosphorylation of CREB might play a more important role in the process.
Tài liệu tham khảo
Hwang HW, Mendell JT: MicroRNAs in cell proliferation, cell death, and tumorigenesis. British J Cancer. 2006, 94: 776-780. 10.1038/sj.bjc.6603023.
Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L: lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011, 477: 295-300. 10.1038/nature10398.
Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P: Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet. 2011, 43: 621-629. 10.1038/ng.848.
Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A: Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009, 106: 11667-11672. 10.1073/pnas.0904715106.
Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, Garber M, Curran M, Onder T, Agarwal S: Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet. 2010, 42: 1113-1117. 10.1038/ng.710.
Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA: A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011, 472: 120-124. 10.1038/nature09819.
Mercer TR, Dinger ME, Mattick JS: Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009, 10: 155-159. 10.1038/nrg2521.
Wang KC, Chang HY: Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011, 43: 904-914. 10.1016/j.molcel.2011.08.018.
Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I: A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011, 147: 358-369. 10.1016/j.cell.2011.09.028.
Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, StLaurent G, Kenny PJ, Wahlestedt C: Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008, 14: 723-730. 10.1038/nm1784.
Qureshi IA, Mattick JS, Mehler MF: Long non-coding RNAs in nervous system function and disease. Brain Res. 2010, 1338: 20-35.
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010, 464: 1071-1076. 10.1038/nature08975.
Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, Cui H: Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature. 2008, 451: 202-206. 10.1038/nature06468.
Yang F, Zhang L, Huo XS, Yuan JH, Xu D, Yuan SX, Zhu N, Zhou WP, Yang GS, Wang YZ: Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011, 54: 1679-1689. 10.1002/hep.24563.
Kim HP, Leonard WJ: CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med. 2007, 204: 1543-1551.
Zhang L, Zhao Y: The regulation of Foxp3 expression in regulatory CD4(+)CD25(+)T cells: multiple pathways on the road. J Cell Physiol. 2007, 211: 590-597. 10.1002/jcp.21001.
Baumgart DC, Carding SR: Inflammatory bowel disease: cause and immunobiology. Lancet. 2007, 369: 1627-1640. 10.1016/S0140-6736(07)60750-8.
Sakaguchi S, Yamaguchi T, Nomura T, Ono M: Regulatory T cells and immune tolerance. Cell. 2008, 133: 775-787. 10.1016/j.cell.2008.05.009.
Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat immunol. 2003, 4: 330-336.
Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003, 299: 1057-1061. 10.1126/science.1079490.
Ochs HD, Ziegler SF, Torgerson TR: FOXP3 acts as a rheostat of the immune response. Immunol Rev. 2005, 203: 156-164. 10.1111/j.0105-2896.2005.00231.x.
Boden EK, Snapper SB: Regulatory T cells in inflammatory bowel disease. Curr Opin Gastroenterol. 2008, 24: 733-741. 10.1097/MOG.0b013e328311f26e.
Harvey RF, Bradshaw JM: A simple index of Crohn's-disease activity. Lancet. 1980, 1: 514-
Satsangi J, Silverberg MS, Vermeire S, Colombel JF: The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006, 55: 749-753. 10.1136/gut.2005.082909.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.
Wang Y, Liu XP, Zhao ZB, Chen JH, Yu CG: Expression of CD4+ forkhead box P3 (FOXP3) + regulatory T cells in inflammatory bowel disease. J Dig Dis. 2011, 12: 286-294. 10.1111/j.1751-2980.2011.00505.x.
Saruta M, Yu QT, Fleshner PR, Mantel PY, Schmidt-Weber CB, Banham AH, Papadakis KA: Characterization of FOXP3 + CD4+ regulatory T cells in Crohn's disease. Clin Immunol. 2007, 125: 281-290. 10.1016/j.clim.2007.08.003.
Ochaion A, Bar-Yehuda S, Cohen S, Barer F, Patoka R, Amital H, Reitblat T, Reitblat A, Ophir J, Konfino I: The anti-inflammatory target A(3) adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn's disease. Cell Immunol. 2009, 258: 115-122. 10.1016/j.cellimm.2009.03.020.
von Boehmer H, Nolting J: What turns on Foxp3?. Nat Immunol. 2008, 9: 121-122. 10.1038/ni0208-121.
Wen AY, Sakamoto KM, Miller LS: The role of the transcription factor CREB in immune function. J Immunol. 2010, 185: 6413-6419. 10.4049/jimmunol.1001829.
Sakaguchi S, Miyara M, Costantino CM, Hafler DA: FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010, 10: 490-500. 10.1038/nri2785.
Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J: DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008, 38: 1654-1663. 10.1002/eji.200838105.
Polansky JK, Schreiber L, Thelemann C, Ludwig L, Kruger M, Baumgrass R, Cording S, Floess S, Hamann A, Huehn J: Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J Mol Med (Berl). 2010, 88: 1029-1040. 10.1007/s00109-010-0642-1.
Yang C, Li X, Wang Y, Zhao L, Chen W: Long non-coding RNA UCA1 regulated cell cycle distribution via CREB through PI3-K dependent pathway in bladder carcinoma cells. Gene. 2012, 496: 8-16. 10.1016/j.gene.2012.01.012.
Wang J, Liu X, Wu H, Ni P, Gu Z, Qiao Y, Chen N, Sun F, Fan Q: CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res. 2010, 38: 5366-5383. 10.1093/nar/gkq285.
Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM: Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells. J Immunol. 2012, 189: 2084-2088. 10.4049/jimmunol.1200774.
Wang Z, Hong J, Sun W, Xu G, Li N, Chen X, Liu A, Xu L, Sun B, Zhang JZ: Role of IFN-gamma in induction of Foxp3 and conversion of CD4+ CD25- T cells to CD4+ Tregs. J Clin Invest. 2006, 116: 2434-2441.