美國洛克菲勒大學(xué)和密歇根大學(xué)醫(yī)學(xué)院的一項(xiàng)研究表明,，基因組中某些DNA片段——增強(qiáng)子(genome enhancers)能夠調(diào)控機(jī)體產(chǎn)生抵抗病菌的抗體,，以防止許多病毒和細(xì)菌的入侵。這項(xiàng)研究發(fā)表在本月的Journal of Experimental Medicine雜志上,，該研究或許可以解決一個(gè)困擾科學(xué)家?guī)资甑膯栴}——DNA增強(qiáng)子在免疫系統(tǒng)中如何發(fā)揮作用,。
增強(qiáng)子是一類小片段的DNA，能夠遠(yuǎn)距離調(diào)控基因的表達(dá),。由于增強(qiáng)子是遠(yuǎn)距離調(diào)控,，因此科學(xué)家一般很難對其研究。但是免疫增強(qiáng)子(immunoglobulin enhancers)是一個(gè)特例,，因?yàn)樗话阍诳拷旧w末端的位置,。
密西根大學(xué)醫(yī)學(xué)院的Wesley Dunnick教授并不直接在增強(qiáng)子上進(jìn)行修改，而是建立了一種新方法——將增強(qiáng)子及其鄰近的抗體基因整體轉(zhuǎn)移到一種人工細(xì)菌染色體(artificial bacterial chromosome)上,，這樣即可隨意對增強(qiáng)子進(jìn)行刪減或突變,，隨后他將這種修飾后的人工染色體重新插入并整合到老鼠基因組中，并研究這些修飾后的增強(qiáng)子對產(chǎn)生抗體的影響,。
為了應(yīng)答無數(shù)的外界抗原的入侵,，免疫系統(tǒng)必須產(chǎn)生相應(yīng)的各類抗體，但由于細(xì)胞中DNA的數(shù)量是有限的,，因此,，產(chǎn)生抗體的B細(xì)胞需要通過體細(xì)胞突變(somatic hypermutation)或類別轉(zhuǎn)換重組(class switch recombination)等過程轉(zhuǎn)變或重組抗體基因。
在該研究中研究人員發(fā)現(xiàn),，攜帶著含有抗體基因的人工染色體的老鼠的表現(xiàn)與一般老鼠相似：都可通過轉(zhuǎn)變或重組抗體基因產(chǎn)生針對特定抗原的高特異性抗體,，但特別的一點(diǎn)是，該過程需要增強(qiáng)子的參與,，如果缺失增強(qiáng)子,，細(xì)胞雖能轉(zhuǎn)錄和翻譯抗體基因，但無法重新轉(zhuǎn)變或重組抗體基因,。
這項(xiàng)研究表明,，抗體基因的增強(qiáng)子對免疫系統(tǒng)發(fā)揮功能至關(guān)重要，增強(qiáng)子發(fā)生突變將會(huì)是個(gè)體易受到病原體的感染。（生物谷Bioon.com）
生物谷推薦原始出處：
The Journal of Experimental Medicine, Vol. 206, No. 12, 2613-2623 doi:10.1084/jem.20091280
Switch recombination and somatic hypermutation are controlled by the heavy chain 3' enhancer region
Wesley A. Dunnick1, John T. Collins1, Jian Shi1, Gerwin Westfield1, Clinton Fontaine1, Paul Hakimpour2, and F. Nina Papavasiliou2
1 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48103
2 Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10021
Both class switch recombination (CSR) and somatic hypermutation (SHM) require transcription and the trans-acting factor activation-induced cytidine deaminase (AID), and must be up-regulated during antigen-dependent differentiation of B lymphocytes. To test the role of the heavy chain 3' enhancers in both CSR and SHM, we used a BAC transgene of the entire heavy chain constant region locus. Using Cre-loxP recombination to delete a 28-kb region that contains the four known 3' heavy chain enhancers, we isolated lines of BAC transgenic mice with an intact heavy chain locus and paired lines in the same chromosomal insertion site lacking the 3' enhancers. Intact heavy chain transgenes undergo CSR to all heavy chain genes and mutate their transgenic VDJ exon. In paired transgenes lacking the 3' enhancer region, CSR to most heavy chain genes is reduced to 1% of the levels for intact heavy chain loci; SHM is also reduced. Finally, we find that in B cells with a transgene lacking the 3' enhancers, interchromosomal recombination between the transgenic VDJ exon and the endogenous heavy chain C genes is more easily detected than CSR within the transgene.
