生物通报道：来自美国国家卫生研究院（National Institutes of Health，NIH）国立心脏，肺和血液协会分子免疫学实验室的华人科学家赵可吉（Keji Zhao，通讯作者）领导的研究小组为了了解T细胞特有的基因表达动力学事件，绘制了一张活性组蛋白修饰全基因组图谱。这一研究成果公布在最新一期（10月16日）《美国国家科学院院刊》PNAS杂志上。

链接：
Published online before print October 16, 2006
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0607617103
The genomic landscape of histone modifications in human T cells 
[Abstract]

在这一研究中，Zhao等人通过绘制活性组蛋白修饰全基因组图谱（包含了人类原代T细胞的组蛋白H3 K9/K14 diacetylation (H3K9acK14ac), H3 K4 trimethylation (H3K4me3), 和抑制性组蛋白修饰H3 K27 trimethylation (H3K27me3)），从中发现H3K9acK14ac和H3K4me3与T细胞功能和发育必要基因关系密切，而H3K27me3则是与其它类型细胞发育有关的沉默基因有关联。

而且令研究人员惊讶的是，他们发现与所有这些组蛋白修饰有关的基因启动子多达3,330个，这些基因表达水平不但与活性H3K4me3和抑制性H3K27me3的完全修饰有关，与其相对水平也有关系。这些数据表明快速可诱导基因与H3乙酰化以及H3K4me3修饰联系在了一起，这说明它们可能是活性平衡的一个染色质结构。

除此之外，研究人员还染色质区域的一个亚区域有高水平的H3K4me3和H3K27me3，而H3K9acK14ac表达说较低，因此这些区域的染色质修饰方式与其它区域有很大的不同，也许可以代表一类特殊的染色质区域。
（生物通：万纹）

附：
Keji Zhao 

Education and Professional Training

Postdoctoral Fellow, Stanford University, Damon Runyon-Walter Winchel Cancer Research Postdoctoral Fellow, Supervisor: Professor Gerald.R. Crabtree, 1999 

PhD, Molecular Biology, University of Geneva, Switzerland, 1996 
Advisor: Professor Ulrich.K. Laemmli 

Organic Chemistry, Southern Illinois University at Carbondale, 1990 

MS, Organic Chemistry, Northeast Normal University, Changchun, China, 1985 
Advisor: Professors Yunhong Sun and Huade Pan 

BS, Chemistry, Changwei Normal College, Weifang, China, 1980 

Research Overview

Eukaryotic DNA is organized into a highly ordered chromatin structure that ultimately controls the expression potential of a eukaryotic genome. The status of chromatin modification is mitotically stable and preserves information that determines a cell’s identity. Our research is focused on how the chromatin structure is modified during cellular development and how the modification determines the expression potential of a specific genomic locus. 

The chromatin structure can be modified (or remodeled) by two major mechanisms. One is the activity of ATP-utilizing enzymes prototyped by the yeast SWI/SNF complex that was identified by mating type switch and sucrose non-fermentation phenotypes in yeast. The complex uses ATP-derived energy to alter the DNA-histone interactions. The other mechanism is the post-translational modification of histones including acetylation, methylation, ubiquitination, and phosphorylation, which provides specific recognition platforms for various regulatory enzymes on the chromatin substrate. 

BRG1 is the mammalian ortholog of yeast SNF2 that is the ATPase subunit of the yeast SWI/SNF complex. Association of 10 to 12 other subunits with BRG1 forms the 2-MDa mammalian SWI/SNF-like BAF complex. BAF complex remodels nucleosomal structure in vitro. However, its function and mechanisms in vivo are elusive. Mutations of the complex have been correlated with various cancers, suggesting it can act as a tumor suppressor. This function has been attributed to its direct physical interaction with the tumor suppressor protein, pRb, which is assumed to be required for the activity of pRb. We have demonstrated that the BAF complex regulates the activity of pRb via regulating the expression of the cell cycle inhibitor p21. We have also found that the complex is required for the cellular antiviral activities and regulates hundreds of interferon-inducible genes. We are currently studying the mechanisms by which the BAF complex recognizes its target sites. 

Post-translational modification of histone tails is a complex language encoding information for expression of a genome. To decipher the language of histone modifications, we have developed an unbiased Genome-wide MApping Technique (GMAT) to analyze the global histone modifications. The method has been successfully used to identify the genome-wide target sites of the histone H3 acetylase GCN5 in yeast. Application of this technique to human T cells has allowed to us discover “histone acetylation islands” as transcriptional and chromatin regulatory elements. The 46,000 acetylation islands in T cells may represent the first experimentally identified regulatory network that mediate T cells development and differentiation. An interactive high-resolution map of the histone H3K9acK14ac in human T cells is linked to the UCSC genome browser. We are using GMAT to (1) identify patterns of histone modification in the human genome, (2) study how the patterns are established; (3) reveal the relationship between histone modification patterns and gene expression profiles; and (4) to understand diseases resulting from mis-regulation of the epigenetic modifications. 

Novel mechanisms of chromatin remodeling are emerging. We have recently demonstrated that the formation of non-classical Z-DNA structure plays a critical role in the BRG1-induced chromatin remodeling and activation of the CSF1 gene. This is the first biological function identified for Z-DNA structure that was discovered almost thirty years ago. We are currently studying if the Z-DNA structure plays a general role in modifying chromatin structure in the human genome.