最新一期的世界頂級(jí)學(xué)術(shù)期刊《美國國家科學(xué)院（PNAS）》發(fā)布了上海交大研究團(tuán)隊(duì)一項(xiàng)重要成果,。上海交大系統(tǒng)生物醫(yī)學(xué)研究院教授吳強(qiáng)的科研團(tuán)隊(duì)發(fā)現(xiàn)一種特殊蛋白質(zhì)調(diào)控機(jī)理,，闡明了原鈣粘蛋白家族在大腦中細(xì)胞特異性表達(dá)的分子機(jī)制,。這一研究成果對(duì)科學(xué)家破解人類基因組的編碼調(diào)控機(jī)制,，以及破解精神疾病發(fā)病機(jī)理將產(chǎn)生深遠(yuǎn)影響,。
上海交大系統(tǒng)生物醫(yī)學(xué)研究院教授吳強(qiáng)5日介紹,，人腦含有上千億個(gè)不同的神經(jīng)細(xì)胞,，每個(gè)神經(jīng)細(xì)胞又形成上萬個(gè)特異性突觸連接,。如同世界上沒有兩片完全相同的樹葉一樣,，人腦的神經(jīng)細(xì)胞也各不相同，而構(gòu)成其差異的“身份密碼”就是由“原鈣粘蛋白群”決定的,。吳強(qiáng)說,，如精神分裂癥、自閉癥,、抑郁癥,，甚至腦腫瘤等大腦疾病，都可能是因?yàn)樯窠?jīng)細(xì)胞某種蛋白質(zhì)表達(dá)出現(xiàn)問題,。如今這一“身份密碼”如何產(chǎn)生得以破解,，對(duì)于研究此類疾病機(jī)理將起到關(guān)鍵作用。
吳強(qiáng)形容說,，人的每個(gè)基因都有若干個(gè)激發(fā)其活性的“發(fā)動(dòng)機(jī)”,，稱為“啟動(dòng)子”；還有一個(gè)增強(qiáng)其活性的“加速器”,，稱為“增強(qiáng)子”,。在一條DNA染色體上，它們往往相隔甚遠(yuǎn),，它們?nèi)绾巫赃x組合決定了細(xì)胞的差異性,，而它們?nèi)绾芜x擇、連結(jié),，是由“絕緣子結(jié)合蛋白CTCF”和“染色體粘連蛋白Cohesin”決定的,。二者都至關(guān)重要，不可或缺,，它們控制著原鈣原蛋白“啟動(dòng)子”的選擇,，組成每個(gè)神經(jīng)細(xì)胞獨(dú)特的“身份密碼”。
國際評(píng)審專家對(duì)于該研究給予高度評(píng)價(jià),，認(rèn)為其揭示的調(diào)控機(jī)制在基因表達(dá)調(diào)控領(lǐng)域具有廣泛意義,。專家認(rèn)為，進(jìn)一步的研究將有助于人們對(duì)復(fù)雜神經(jīng)網(wǎng)絡(luò)形成機(jī)理的理解,，并促進(jìn)對(duì)腦腫瘤,、精神分裂癥、自閉癥等大腦疾病發(fā)病機(jī)制研究,。（生物谷Bioon.com）
doi:10.1073/pnas.1219280110
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CTCF/cohesin-mediated DNA looping is required for protocadherin {alpha} promoter choice
Ya Guo, Kevin Monahan, Haiyang Wu, Jason Gertz, Katherine E. Varley, Wei Li, Richard M. Myers, Tom Maniatis, and Qiang Wu
The closely linked human protocadherin (Pcdh) α, β, and γ gene clusters encode 53 distinct protein isoforms, which are expressed in a combinatorial manner to generate enormous diversity on the surface of individual neurons. This diversity is a consequence of stochastic promoter choice and alternative pre-mRNA processing. Here, we show that Pcdhα promoter choice is achieved by DNA looping between two downstream transcriptional enhancers and individual promoters driving the expression of alternate Pcdhα isoforms. In addition, we show that this DNA looping requires specific binding of the CTCF/cohesin complex to two symmetrically aligned binding sites in both the transcriptionally active promoters and in one of the enhancers. These findings have important implications regarding enhancer/promoter interactions in the generation of complex Pcdh cell surface codes for the establishment of neuronal identity and self-avoidance in individual neurons.
