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Allele-specific expression patterns of interleukin-2 and Pax-5 revealed by a sensitive single-cell RT-PCR analysis

2000; Elsevier BV; Volume: 10; Issue: 13 Linguagem: Inglês

10.1016/s0960-9822(00)00565-0

1879-0445

Kristina Rhoades, N. P. Singh, Itamar Simon, Barbara Glidden, Howard Cedar, Andrew Chess,

Genetic Syndromes and Imprinting

Autosomal genes that are subject to random allelic inactivation (RAI), like imprinted genes [1Tilghman S.M. The sins of the fathers and mothers genomic imprinting in mammalian development.Cell. 1999; 96: 185-193Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar] and genes subject to X-inactivation [2Panning B. Jaenisch R. RNA and the epigenetic regulation of X chromosome inactivation.Cell. 1998; 93: 305-308Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar], require mechanisms that dictate the differential transcriptional regulation of two sequence-identical alleles. RAI genes include olfactory receptor genes [3Chess A. Simon I. Cedar H. Axel R. Allelic inactivation regulates olfactory receptor gene expression.Cell. 1994; 78: 823-834Abstract Full Text PDF PubMed Scopus (834) Google Scholar], and the various genes encoding antigen receptors on lymphocytes (immunoglobulin genes, T cell receptor genes and NK receptor genes [4Chess A. Olfactory receptor gene regulation.Adv Immunol. 1998; 69: 437-447Crossref PubMed Google Scholar, 5Tonegawa S. Somatic generation of antibody diversity.Nature. 1983; 302: 575-581Crossref PubMed Scopus (3018) Google Scholar, 6von Boehmer H. T cell development and selection in the thymus.Bone Marrow Transplant. 1992; 1: 46-48Google Scholar, 7Held W. Roland J. Raulet D.H. Allelic exclusion of Ly49-family genes encoding class I MHC-specific receptors on NK cells.Nature. 1995; 376: 355-358Crossref PubMed Scopus (162) Google Scholar]). These observations raise the possibility that other genes might be similarly regulated. Moreover, an interesting possibility is that certain genes might be monoallelically expressed in some cells and biallelically expressed in others. Recently, reports of monoallelic expression of interleukin-2 (IL-2) [8Hollander G.A. Zuklys S. Morel C. Mizoguchi E. Mobisson K. Simpson S. et al.Monoallelic expression of the interleukin-2 locus.Science. 1998; 279: 2118-2121Crossref PubMed Scopus (202) Google Scholar, 9Naramura M. Hu R.J. Gu H. Mice with a fluorescent marker for interleukin 2 gene activation.Immunity. 1998; 9: 209-216Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar] and IL-4 [10Bix M. Locksley R.M. Independent and epigenetic regulation of the interleukin-4 alleles in CD4+ T cells.Science. 1998; 281: 1352-1354Crossref PubMed Scopus (202) Google Scholar, 11Riviere I. Sunshine M.J. Littman D.R. Regulation of IL-4 expression by activation of individual alleles.Immunity. 1998; 9: 217-228Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar] have raised the possibility that the cytokine gene family may be subject to monoallelic expression. Another report suggests that the gene encoding the transcription factor Pax-5, which is involved in B-cell (and cerebellar) development [12Urbanek P. Wang Z.Q. Fetka I. Wagner E.F. Busslinger M. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP.Cell. 1994; 79: 901-912Abstract Full Text PDF PubMed Scopus (653) Google Scholar, 13Adams B. Dorfler P. Aguzzi A. Kozmik Z. Urbanek P. Maurer-Fogy I. Busslinger M. Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis.Genes Dev. 1992; 6: 1589-1607Crossref PubMed Scopus (449) Google Scholar], is also subject to monoallelic expression [14Nutt S. Vambrie S. Steinlein P. Kozmik Z. Rolink A. Weith A. Busslinger M. Independent regulation of the two Pax5 alleles during B-cell development.Nat Genet. 1999; 21: 390Crossref PubMed Scopus (115) Google Scholar]. Using a novel single-cell reverse transcription-polymerase chain reaction (RT-PCR) approach, we have analyzed the IL-2 and Pax-5 genes in mice. We found that IL-2 is monoallelically transcribed in some T cells and biallelically transcribed in others, raising interesting questions regarding cytokine gene regulation. Additionally, our analyses suggest that Pax-5 is consistently biallelically transcribed. Thus, the IL-2 gene and other cytokine genes may be regulated in a stochastic manner that results in 0, 1 or 2 alleles of a given cytokine gene expressed in each T cell. This type of regulation could account for the wide variety of different combinations of cytokine genes expressed in individual T cells and therefore plays a role in the generation of T cells with a range of different effector functions.