像繩珠一樣沿著整個(gè)染色體進(jìn)行排列的核小體，是染色體的最基本單位,。那么,，是什么決定核小體在何時(shí)、何處,，怎樣沿著DNA鏈進(jìn)行定位的呢,？魏茲曼研究院今天宣稱，該院研究人員破譯了決定核小體如何在DNA鏈上進(jìn)行定位的基因代碼,。這些發(fā)現(xiàn)發(fā)表在7月9日的《Nature》雜志上,。
核小體在DNA上的精確定位對細(xì)胞日常功能的發(fā)揮起重要作用，當(dāng)相鄰核小體之間的自由區(qū)域只有約20個(gè)堿基長時(shí),，單個(gè)核小體大約包含著150個(gè)堿基對,。正是在這些核小體自由區(qū)域，才能進(jìn)行遺傳信息的復(fù)制,。
多年以來,，科學(xué)家并不認(rèn)為活細(xì)胞中核小體的位置是由遺傳排序自身控制的。魏茲曼研究院的埃蘭·賽杰爾博士等研究人員則設(shè)法證明了,，DNA的排序確實(shí)對如何放置核小體的“分區(qū)制”信息進(jìn)行了編碼,。另外，他們還分析出這個(gè)代碼的特征,，并利用僅利用DNA排序,，就精確地預(yù)測出酵母菌細(xì)胞中大量核小體的位置。
為完成這項(xiàng)研究,，賽杰爾等人檢查了大約200個(gè)不同核小體在DNA中的位置,，并且從它們的排序中尋找共同之處。他們用數(shù)學(xué)方法分析核小體排序之間的相似之處,，最后找到了一種特殊的“代碼世界”,。這個(gè)“代碼世界”是由一個(gè)在排序上每隔10個(gè)堿基出現(xiàn)的周期性信號組成。這個(gè)信號有規(guī)則地循環(huán),，幫助DNA片斷急劇彎曲成能夠形成核小體所需要的球形形狀。為識別這個(gè)核小體的定位代碼,，研究人員利用概率模型,，來分析被核小體約束著的排序,，并且開發(fā)了一個(gè)計(jì)算機(jī)算法，來預(yù)測一個(gè)整個(gè)染色體上核小體的編碼組織,。
一個(gè)困擾分子生物學(xué)家的難題是,，細(xì)胞是如何指導(dǎo)轉(zhuǎn)錄因子到達(dá)它們在DNA上的合適位置，而不是那些相似卻在功能上不相關(guān)的地點(diǎn),？研究人員發(fā)現(xiàn),，一個(gè)與結(jié)合位置有功能關(guān)聯(lián)的基礎(chǔ)信息，部分存在于核小體定位代碼中：想要到達(dá)的地點(diǎn)在核小體之間的染色體片斷上被發(fā)現(xiàn),，從而允許它們接受不同轉(zhuǎn)錄因子的引導(dǎo),。因此，如果用相同結(jié)構(gòu)的假結(jié)合位置就能誤導(dǎo)轉(zhuǎn)錄因子,，從而幫助科學(xué)家找出這種結(jié)構(gòu),。
研究人員認(rèn)為，由于形成核小體核心的蛋白質(zhì)存在于自然界大多數(shù)進(jìn)化物種中,，他們識別出來的遺傳代碼應(yīng)該存在于包括人類在內(nèi)的許多有機(jī)體之中,。有些疾病，如癌癥等,，就是由基因突變以及它們組織染色體的方式引起的,。這種突變過程可能受到DNA對于不同蛋白質(zhì)的可接近性，以及在細(xì)胞核中DNA組織的影響,。因此,，研究人員相信，他們發(fā)現(xiàn)的核小體的定位代碼,，有助于揭示許多疾病的病理,。
DNA這種又長又細(xì)的分子負(fù)載著我們的遺傳信息。DNA在細(xì)胞核中被蛋白包圍著并被壓縮成微小的球體——核小體（nucleosome）,。這些珠狀的核小體成串的沿著染色體分布,，染色體自己折疊和組裝以適合細(xì)胞核的大小。是什么決定了核小體沿著DNA序列定位的方式,、時(shí)間和地點(diǎn)的呢,？Eran Segal博士和Weizmann科學(xué)研究所計(jì)算機(jī)科學(xué)與應(yīng)用數(shù)學(xué)系的研究生Yair Field已經(jīng)成功的破解了編碼核小體在DNA鏈上的定位的遺傳密碼。他們的合作者包括來自芝加哥西北大學(xué)的同事,。
核小體在DNA分子上的精確位置被認(rèn)為在細(xì)胞每天的活動(dòng)中具有十分重要的作用，由于DNA被包裝進(jìn)核小體中,，阻斷了許多蛋白與DNA的接觸機(jī)會(huì),，包括那些負(fù)責(zé)一些最基本的生命過程的蛋白。這些被隔絕的蛋白中有的是起始DNA復(fù)制、轉(zhuǎn)錄和DNA修復(fù)的因子,。因此,，核小體的位置分布決定了這些過程能不能發(fā)生,。這些過程所受的限制相當(dāng)?shù)亩啵捍蟛糠諨NA包裝進(jìn)核小體中,。單個(gè)核小體包含大約150個(gè)遺傳堿基,，而相鄰的核小體之間的自由區(qū)域僅僅為20個(gè)堿基的長度,。就是在這些核小體之間的自由區(qū)域,，像轉(zhuǎn)錄等過程才能起始,。
許多年以來,，是否核小體在活細(xì)胞的位置受自身的遺傳序列所控制呢,？科學(xué)家們一直未能達(dá)成共識,。Segal和他的同事們成功地證明DNA序列的確編碼著放置核小體的“區(qū)域”信息,。同時(shí),，他們僅僅利用DNA序列破解了這些密碼,，并能準(zhǔn)確地預(yù)言酵母細(xì)胞中大量核小體的位置,。
Segal和他的同事們通過研究大約200個(gè)不同的核小體在DNA上的位置并觀察它們的序列是之間是否存在共性來完成這項(xiàng)發(fā)現(xiàn)工作的。數(shù)學(xué)分析揭示了這些核小體包裝的序列的相似性,，并且最終發(fā)現(xiàn)了一種特殊的“密碼語言”,。這種“密碼語言”由序列上出現(xiàn)的每10個(gè)堿基的周期信號組成,。這種信號的規(guī)則重復(fù)幫助DNA片斷劇烈的彎曲成核小體所需的球狀,。為了確證這些核小體的定位密碼,，研究小組利用概率模型來獲得被核小體包圍的DNA序列,，然后他們開發(fā)了一種計(jì)算機(jī)算法來預(yù)言整個(gè)染色體中的核小體的編碼組織方式,。
該研究小組的發(fā)現(xiàn)為另一個(gè)困惑分子生物學(xué)家們很久的神秘事物——細(xì)胞是怎樣指導(dǎo)轉(zhuǎn)錄因子結(jié)合到DNA上預(yù)想的位點(diǎn)的呢，而不是到達(dá)基因組中其他一些序列相似但功能毫不相關(guān)的位點(diǎn)上——提供了深入的理解,。這些短的結(jié)合位點(diǎn)自身不包含足夠的讓轉(zhuǎn)錄因子識別它們的信息,。科學(xué)家們表示關(guān)于結(jié)合位點(diǎn)的功能相關(guān)的基本信息至少有一部分是編碼在核小體定位密碼中：在核小體之間的自由區(qū)域片斷中發(fā)現(xiàn)這些預(yù)期的結(jié)合位點(diǎn),，因此,，使得它們能夠接觸到各種不同的轉(zhuǎn)錄因子,。相反,，一些具有相同結(jié)構(gòu)的偽似位點(diǎn)可能包含在核小體中,，因此轉(zhuǎn)錄因子難以接近,。
既然來自核小體核心的蛋白在自然界進(jìn)化中是十分保守的,，科學(xué)家因此相信他們所證實(shí)的這些遺傳密碼應(yīng)該在包括人類在內(nèi)的許多生物中是十分保守的,。一些疾病,，像癌癥,，一般都會(huì)伴隨著或者由DNA的突變導(dǎo)致,。這種突變的過程可能會(huì)影響DNA與各種蛋白的接觸機(jī)會(huì)和細(xì)胞核中的DNA組裝。因此,，科學(xué)家們相信他們發(fā)現(xiàn)的核小體定位密碼可以在將來幫助他們理解這些疾病的發(fā)病機(jī)理。
英文原文：
Scientists discover a genetic code for organizing DNA within the nucleus
DNA ?the long, thin molecule that carries our hereditary material ?is compressed around protein scaffolding in the cell nucleus into tiny spheres called nucleosomes. The bead-like nucleosomes are strung along the entire chromosome, which is itself folded and packaged to fit into the nucleus. What determines how, when and where a nucleosome will be positioned along the DNA sequence? Dr. Eran Segal and research student Yair Field of the Computer Science and Applied Mathematics Department at the Weizmann Institute of Science have succeeded, together with colleagues from Northwestern University in Chicago, in cracking the genetic code that sets the rules for where on the DNA strand the nucleosomes will be situated. Their findings appeared today in Nature.
The precise location of the nucleosomes along the DNA is known to play an important role in the cell's day to day function, since access to DNA wrapped in a nucleosome is blocked for many proteins, including those responsible for some of life's most basic processes. Among these barred proteins are factors that initiate DNA replication, transcription (the transfer of genetic information from DNA to RNA) and DNA repair. Thus, the positioning of nucleosomes defines the segments in which these processes can and can't take place. These limitations are considerable: Most of the DNA is packaged into nucleosomes. A single nucleosome contains about 150 genetic bases (the "letters" that make up a genetic sequence), while the free area between neighboring nucleosomes is only about 20 bases long. It is in these nucleosome-free regions that processes such as transcription can be initiated.
For many years, scientists have been unable to agree whether the placement of nucleosomes in live cells is controlled by the genetic sequence itself. Segal and his colleagues managed to prove that the DNA sequence indeed encodes "zoning" information on where to place nucleosomes. They also characterized this code and then, using the DNA sequence alone, were able to accurately predict a large number of nucleosome positions in yeast cells.
Segal and his colleagues accomplished this by examining around 200 different nucleosome sites on the DNA and asking whether their sequences have something in common. Mathematical analysis revealed similarities between the nucleosome-bound sequences and eventually uncovered a specific "code word." This "code word" consists of a periodic signal that appears every 10 bases on the sequence. The regular repetition of this signal helps the DNA segment to bend sharply into the spherical shape required to form a nucleosome. To identify this nucleosome positioning code, the research team used probabilistic models to characterize the sequences bound by nucleosomes, and they then developed a computer algorithm to predict the encoded organization of nucleosomes along an entire chromosome.
The team's findings provided insight into another mystery that has long been puzzling molecular biologists: How do cells direct transcription factors to their intended sites on the DNA, as opposed to the many similar but functionally irrelevant sites along the genomic sequence? The short binding sites themselves do not contain enough information for the transcription factors to discern between them. The scientists showed that basic information on the functional relevance of a binding site is at least partially encoded in the nucleosome positioning code: The intended sites are found in nucleosome-free segments, thereby allowing them to be accessed by the various transcription factors. In contrast, spurious binding sites with identical structures that could potentially sidetrack transcription factors are conveniently situated in segments that form nucleosomes, and are thus mostly inaccessible.
Since the proteins that form the core of the nucleosome are among the most evolutionarily conserved in nature, the scientists believe the genetic code they identified should also be conserved in many organisms, including humans. Several diseases, such as cancer, are typically accompanied or caused by mutations in the DNA and the way it organizes into chromosomes. Such mutational processes may be influenced by the relative accessibility of the DNA to various proteins and by the organization of the DNA in the cell nucleus. Therefore, the scientists believe that the nucleosome positioning code they discovered may aid scientists in the future in understanding the mechanisms underlying many diseases.
Dr. Eran Segal's research is supported by the Arie and Ida Crown Memorial Charitable Fund and the Estelle Funk Foundation.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,500 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment
