南加州大學(xué)和哈佛醫(yī)學(xué)院的研究人員發(fā)現(xiàn),，單獨的一種蛋白就能夠通過改變一個“優(yōu)雅的基因組舞蹈”模式就能開啟和關(guān)閉
免疫系統(tǒng)的一個關(guān)鍵成分。南加州大學(xué)的華人分子和計算機生物學(xué)教授陳林（Lin Chen）是這個研究組的領(lǐng)頭人,。陳教授表示,，這些結(jié)果將為了解免疫耐受性基礎(chǔ)機制開啟一扇大門。研究的結(jié)果刊登在7月28日的Cell雜志上,。
由于自身免疫疾病如關(guān)節(jié)炎,、過敏等，是在身體的防御應(yīng)答發(fā)生在錯誤的時間或地點時發(fā)作的,，因此免疫系統(tǒng)的開關(guān)是數(shù)十年來自身免疫疾病的一個重點研究課題,。
這個由南加州大學(xué)和哈佛醫(yī)學(xué)院組成的研究組分析了對免疫耐受性很關(guān)鍵的蛋白質(zhì)。免疫耐受性是指弱的免疫系統(tǒng)和過度強悍的免疫應(yīng)答之間的正常平衡,。
研究組證實這種叫做NFAT（活化T細胞核因子）的蛋白質(zhì)與FOXP3（一種調(diào)節(jié)性T細胞的關(guān)鍵因子）合作編排一種對免疫耐受性至關(guān)重要的遺傳程序,。
但是，同一個NFAT在與第二個蛋白質(zhì)家族AP-1搭伴時卻會刺激免疫應(yīng)答,。陳教授表示,，這些發(fā)現(xiàn)為提出已經(jīng)15年的基因表達聯(lián)合控制理論提供了第一個有力的證據(jù)。
根據(jù)這個理論,，一個基因的表達取決于影響它的轉(zhuǎn)錄因子的聯(lián)合,。FOXP3和NFAT就是這樣兩個因子，而人體含大約3000個這樣的轉(zhuǎn)錄因子。研究人員能夠確定出NFAT在與AP1聯(lián)合時活化的單個基因以及在和FOXP3合作時抑制的基因,。
除了闡明這種免疫機制外,，Cell上的這篇文章還是向著更大的生物和醫(yī)學(xué)目標(biāo)——如何關(guān)閉或開啟單個基因邁進的重要一步。這項研究成果也是陳教授歷經(jīng)14年刻苦研究獲得的回報,。
英文原文：
Protein Switches Immune Response
A single protein can turn on and off a key component of the immune system by changing partners in an elegant genomic dance, said researchers at USC and Harvard Medical School.
Because autoimmune diseases such as arthritis and dozens of other illnesses begin when the body’s defenses respond at the wrong time or place, the on-off mechanism for the immune system has been the subject of intense study for decades.
The USC-Harvard team studied proteins critical to immune tolerance, a term for the healthy balance between a weak immune system and an overly aggressive, indiscriminate watchdog.
Lin Chen, professor of molecular and computational biology at USC and lead co-author with Harvard’s Anjana Rao, said the team’s result would “open a big door for people to explain the fundamental mechanism of immune tolerance.”
In the July 28 issue of the science journal Cell, the USC-Harvard group shows that the protein Nuclear Factor of Activated T cells (NFAT), in collaboration with FOXP3, orchestrates a genetic program critical to maintaining immune tolerance.
But the same NFAT, paired with a second family of proteins known as AP-1, instead sharply increases immune response.
Chen said the finding offers the first strong evidence in favor of the 15-year-old “combinatorial control” theory of gene expression.
According to the theory, the specific expression of a gene depends on the combination of “transcription factors” acting on it. Transcription factors help to translate a gene’s instructions into actual proteins. FOXP3 and NFAT are two such factors; the human body contains around 3,000.
“The work provides a structural demonstration of combinatorial control of gene expression,” Chen said. “This is, in my view, the most direct demonstration that this is indeed happening in nature.”
The researchers were able to identify single genes that were activated by NFAT in combination with AP-1 and suppressed by NFAT with FOXP3.
Beyond shedding light on the immune system, the Cell paper may advance biology and medicine toward a much larger goal: how to turn single genes on or off.
“This [result] has far-reaching implications for understanding the principles of signal transduction and transcriptional networks of living cells,” Chen said.
The Cell paper, which Chen describes as spanning 14 years of laboratory work, builds on a result his group published in Nature in 1998.
Chen’s postdoctoral associates Yongqing Wu and Aidong Han are co-authors on the Cell paper. All three moved to USC recently from the University of Colorado at Boulder.
Researchers from the University of Washington in Seattle also contributed to the paper.
Funding for the team’s research came from the National Institutes of Health, the W.M. Keck Foundation, the Juvenile Diabetes Research Foundation and the American Diabetes Association.
