Nature，Science两项染色体研究新成果

　　

生物通报道：染色体是基因的载体，各种基因呈直线排列在各染色体上。染色体的重要性不言而喻，多年来科学家们都希望能破解这种关键物质的分子机理，近期发表在Science和Nature上的两篇文章分别在这方面取得了重要进展。

第一个研究小组利用染色质特征来解读基因组，他们利用多种人类细胞类型中各种不同组蛋白标记的染色质图，分辨不同染色质状态，这对于解答人类疾病具有意义。

来自哈佛大学，霍德华休斯医学院等处的研究人员提供了多种人类细胞类型中各种不同组蛋白标记的染色质图一览，利用所获得的这些数据，有可能来识别不同染色质状态，它们相应于不同调控元素，如被抑制的和活跃的启动子、增强子和绝缘子。几种与疾病相关的单核苷酸多态性被发现与调控元素重叠。这项工作对于了解人类疾病、尤其对于解读“全基因组关联研究”的结果有意义。

另外来自宾夕法尼亚大学的研究人员通过一种新的实验技术，对基因组中所有成分实现高度控制，生成均匀一致的染色质串珠结构，并开发出分析染色体结构的计算机工具，揭示染色体复杂的组装过程。

染色体由DNA链和相关蛋白质缠绕弯曲，高度压缩包装而成。研究小组首先从酵母菌细胞中提取完整的DNA染色体组，经过培养提纯，然后加入相等分量经纯化的组蛋白（DNA与组蛋白的重量比例固定为1∶1）。组蛋白是DNA链缠绕成染色体的基本材料，这样包装过程就开始了。

经过包装后，细长的DNA基因链包围着一颗颗组蛋白形成串珠一样称为核小体的小结，均匀分布在未打结的DNA链上。核小体是一种染色质结构，进一步卷曲压缩则成为染色体。之前其他研究显示，组蛋白和DNA也能各自沿着DNA链制造一些核小体结点，但这些串珠的整体结构却和细胞内形成的染色质大不一样。

研究小组找到了一种新方法，在实验中加入了酵母菌提取物和ATP，染色质改造酶从ATP中提取了必须的能量，沿着DNA重新配置核小体，重新构造出与细胞内染色质一样的人造染色质结构。最关键的是，研究小组还开发出一种计算机图形组装算法，成为从外部研究染色体成分的有力工具，这样，科学家就能“看到”酵母菌细胞中超过6万多个核小体形成染色质的排列方式，从而首次在实验中实际探测到了染色体的结构、功能和它们的组成基因。

原文摘要：

Mapping and analysis of chromatin state dynamics in nine human cell types

Chromatin profiling has emerged as a powerful means of genome annotation and detection of regulatory activity. The approach is especially well suited to the characterization of non-coding portions of the genome, which critically contribute to cellular phenotypes yet remain largely uncharted. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions. Focusing on cell-type-specific patterns of promoters and enhancers, we define multicell activity profiles for chromatin state, gene expression, regulatory motif enrichment and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell-type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for the interpretation of genome-wide association studies. Top-scoring disease single nucleotide polymorphisms are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus suggesting a mechanism for the association. Our study presents a general framework for deciphering cis-regulatory connections and their roles in disease.

A Packing Mechanism for Nucleosome Organization Reconstituted Across a Eukaryotic Genome

Near the 5′ end of most eukaryotic genes, nucleosomes form highly regular arrays that begin at canonical distances from thetranscriptional start site. Determinants of this and other aspects of genomic nucleosome organization have been ascribed tostatistical positioning, intrinsically DNA-encoded positioning, or some aspect of transcription initiation. Here, we provideevidence for a different explanation. Biochemical reconstitution of proper nucleosome positioning, spacing, and occupancylevels was achieved across the 5′ ends of most yeast genes by adenosine triphosphate–dependent trans-acting factors. Thesetranscription-independent activities override DNA-intrinsic positioning and maintain uniform spacing at the 5′ ends of geneseven at low nucleosome densities. Thus, an active, nonstatistical nucleosome packing mechanism creates chromatin organizingcenters at the 5′ ends of genes where important regulatory elements reside.