如今，來自美國(guó)西北大學(xué)物理科學(xué)腫瘤學(xué)中心(Physical Sciences-Oncology Center, PS-OC)的研究人員的三項(xiàng)開創(chuàng)性研究報(bào)道了他們?cè)诜椒ㄉ先〉玫闹匾M(jìn)步,，這將使得人們更好地理解在正常細(xì)胞和癌細(xì)胞中,，基因表達(dá)是如何受到調(diào)控的,，同時(shí)也可能導(dǎo)致人們開發(fā)出更加有效的治療試劑來治療癌癥病人。這三篇論文最近分別在Nature Genetics,、Nature Biotechnology和Nature期刊上,，可能有助于揭示控制基因轉(zhuǎn)錄的機(jī)制。
根據(jù)2006年發(fā)表在Nature期刊上一篇論文,，通信作者 Jonathan Widom和Eran Segal 描述了一種繪制核小體的新方法,。越來越清楚的是，在人體內(nèi),，負(fù)責(zé)DNA組裝成染色質(zhì)的細(xì)胞裝置發(fā)生突變是腫瘤產(chǎn)生的主要推動(dòng)力,。染色質(zhì)是由DNA和蛋白組成的復(fù)合物，當(dāng)遭受壓縮時(shí)會(huì)形成染色體,。這項(xiàng)研究允許人們闡述在細(xì)胞中染色質(zhì)組裝機(jī)制,，從而有助于理解在癌癥中是什么發(fā)生偏差和如何修復(fù)這種偏差。
DNA第一密碼就是DNA遺傳密碼,，能夠確定細(xì)胞蛋白的組成,。2006年前，Widom和Segal就已在這篇論文中報(bào)道,，他們發(fā)現(xiàn)第二種DNA密碼能夠解釋DNA環(huán)繞著組蛋白復(fù)合物形成的線軸樣結(jié)構(gòu)--核小體--的布局,。
根據(jù)2012年5月27日在線發(fā)表在Nature Genetics期刊上的一篇論文和2012年5月20日在線發(fā)表在Nature Biotechnology期刊上的另一篇論文，Segal研究小組開發(fā)出出一種優(yōu)雅的實(shí)驗(yàn)系統(tǒng)：它能夠允許他們準(zhǔn)確地測(cè)量不利于核小體形成的DNA序列對(duì)轉(zhuǎn)錄調(diào)節(jié)的影響,。這項(xiàng)新研究使得他們能夠以一種規(guī)劃好的和系統(tǒng)性的方式,，同時(shí)導(dǎo)入上萬(wàn)個(gè)DNA序列區(qū)域到上萬(wàn)個(gè)活細(xì)胞之中---每個(gè)細(xì)胞導(dǎo)入一個(gè)DNA區(qū)域---，而且能夠在一次實(shí)驗(yàn)中非常精準(zhǔn)地和測(cè)量每個(gè)這樣的變化產(chǎn)生的結(jié)果,。利用這種系統(tǒng),，Segal研究小組證實(shí)促進(jìn)核小體形成的DNA序列確實(shí)對(duì)轉(zhuǎn)錄產(chǎn)生顯著性負(fù)面的影響。<<<相關(guān)論文參見：“Manipulating nucleosome disfavoring sequences allows fine-tune regulation of gene expression in yeast” 和“Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters”,。
根據(jù)第三篇于2012年6月3日在線發(fā)表在Nature期刊上的論文,，研究人員描述了另一種方法上的主要進(jìn)步。這種新技術(shù)允許他們比以前更加高精準(zhǔn)地繪制核小體在基因組上的位置,。這種技術(shù)不僅可以讓人們更好地理解轉(zhuǎn)錄調(diào)控,，同時(shí)它也應(yīng)當(dāng)有助于科學(xué)家們理解DNA生物學(xué)的基因特征。<<<相關(guān)論文參見：“A map of nucleosome positions in yeast at base-pair resolution” (生物谷：Bioon.com)
本文編譯自More code cracking: Three studies help uncover the rules governing gene transcription
doi: 10.1038/nbt.2205
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Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters
Eilon Sharon, Yael Kalma, Ayala Sharp, Tali Raveh-Sadka, Michal Levo, Danny Zeevi, Leeat Keren, Zohar Yakhini, Adina Weinberger & Eran Segal
Despite extensive research, our understanding of the rules according to which cis-regulatory sequences are converted into gene expression is limited. We devised a method for obtaining parallel, highly accurate gene expression measurements from thousands of designed promoters and applied it to measure the effect of systematic changes in the location, number, orientation, affinity and organization of transcription-factor binding sites and nucleosome-disfavoring sequences. Our analyses reveal a clear relationship between expression and binding-site multiplicity, as well as dependencies of expression on the distance between transcription-factor binding sites and gene starts which are transcription-factor specific, including a striking ~10-bp periodic relationship between gene expression and binding-site location. We show how this approach can measure transcription-factor sequence specificities and the sensitivity of transcription-factor sites to the surrounding sequence context, and compare the activity of 75 yeast transcription factors. Our method can be used to study both cis and trans effects of genotype on transcriptional, post-transcriptional and translational control.
