留美女博士Cell子刊解析新机制

　　

生物通报道：早年毕业于北京大学医学院的窦雅丽（Yali Dou, Ph.D.）博士现任密歇根大学副教授，主要研究方向为表观遗传学，组蛋白质组学方面。近期其研究小组在《Molecular Cell》杂志上发表了有关MOF的研究成果，提出了一种新型的调控机制。

MYST组蛋白乙酰转移酶（histone acetyltransferase,HAT）广泛存在于从酵母到人的真核生物中，在真核生物的转录调控中起着重要的作用，这一家族中MOF蛋白在转录活性中扮演着重要的角色——组蛋白H4乙酰转移至K16。MOF基因长1 575 bp(GenBank登录号为DQ442997)，开放阅读框(ORF)长1 326 bp，无内含子，基因编码442个氨基酸，预测蛋白质的分子量为51.4 kD，序列中有HAT核心结构域、锌指结构域和染色质域3个保守的结构域，与其他物种同源基因具有较高的序列相似性。

到目前为止，虽然已经获得了一些MOF调控方面的研究成果，但是在高等真核生物中，科学家们还不是很清楚MOF的调控机制和模式。在这篇文章中，研究人员在两组进化上保守的不同复合物： MSL和MOF-MSL1v1中分析MOF的乙酰转移酶活性。

他们发现虽然这两种MOF复合物在组蛋白H4K16的活性方面存在较小差异，但是在对底物p53这种非组蛋白的作用活性方面却存在极大差异。进一步研究证明MOF-MSF 1v1是一种无论体内，还是体外实验中，p53靶基因获得最佳转录活性的必需因子，这些研究结果提出了一种新型的作用模型：两个MOF复合物能与其它组蛋白修饰活性因子一起调控转录活性的不同阶段。

近期除了这一研究成果外，Cell杂志还刊发了另外一项MOF研究成果，这项成果详细的阐明了H3S10的磷酸化启动基因表达的机制。

首先衔接蛋白（adopter protein 14-3-3）结合到磷酸化的组蛋白上，然后吸引组蛋白乙酰化酶MOF，MOF将组蛋白H4K16乙酰化。H3S10ph/H4K16ac形成的组蛋白密码能够结合BRD4，然后进一步结合转录延伸因子P-TEFb并结合RNA聚合酶II进行基因的转录。
H3S10也是细胞周期中G2期到M期的一个标志，估计又一条完全不同的级联反应，同样是H3S10为什么会结合不同的蛋白进而产生不同的作用。

附：

Yali Dou, Ph.D.
Assistant Professor
Phone: [phone]
FAX: [phone]
[e-mail]

Research Interests:

Heritable changes in gene expression can occur without changes in DNA sequence. It has emerged that histones, the basic components organizing a eukaryotic genome into hierarchical chromatin structures, are major carriers of epigenetic information. The variation is largely encoded by numerous and often evolutionarily conserved covalent modifications of histones, including methylation, acetylation, phosphorylation and ubiquitinylation. Through histone modifications, chromatin modification enzymes act either synergistically or antagonistically in regulating transcription, cell cycle progression, DNA damage repair, replication development, and cellular differentiation. Given the fundamental roles of histone modifications in organizing chromatin and maintaining proper gene expression patterns, it is not surprising that mutations in chromatin modifying enzymes are often found in human disease.

Our broad objectives are to understand the mechanisms for chromatin modifying enzymes to regulate various cellular processes. Using biochemical approaches and mouse models, we are currently focusing on the regulation of histone H3 lysine 4 methyltransferase MLL and histone acetyltransferase MOF, two enzymes that function coordinately in transcription activation. We are also exploring how disruption of their functions leads to carcinogenesis. Given that MLL deregulation (deletion, amplification and translocation) are found in mix lineage leukemias, a thorough understanding of the mechanism for its action and regulation allows us to develop specific inhibitors as novel chemotherapeutic agents.


Brief Biography:

Dr. Dou received a Bachelor's in Medicine from Beijing Medical University, Beijing, China in 1996 and an M.S. (Biology, 1998) and a Ph.D. (Biology, 2000) from the University of Rochester, Rochester, New York. She completed postdoctoral training with Dr. Martin Gorovsky at the University of Rochester from 2000-2002 followed by postdoctoral training in the research laboratory of Dr. Robert Roeder, at The Rockefeller University from 2002-2006.

She was the recipient of the Irvington Institute for Immunological Research Fellowship (204-2007) andis a member of the New York Academy of Sciences and the American Society for Cell Biology.