中国农大校友最新《自然》文章发表突破性研究成果

　　

生物通报道：来自阿拉巴马州大学生物化学与分子遗传学系，细胞生物学系，纪念斯隆－凯特琳癌症中心（Memorial Sloan - Kettering Cancer Center）的研究人员识别出了组蛋白H2A的主要去泛素化（deubiquitination）过程，也证明H2A去泛素化是细胞周期和基因表达的关键步骤。之前的研究虽然揭示了一些组蛋白泛素化的机制，但是并未在H2A去泛素化过程机理研究中获得进展，这一突破性的研究成果目前公布在《Nature》杂志上。

文章的通讯作者是来自阿拉巴马大学的王横滨（Hengbin Wang，音译）副教授，其早年毕业于河北师范大学，于中国农业大学获得博士学位，之后赴日本九州大学进行博士后研究工作，目前任阿拉巴马大学副教授。

组蛋白翻译后修饰在染色体结构和功能方面具有十分重要的意义，扮演着调控者的角色，这些修饰中的组蛋白泛素化（ubiquitination）主要出现在组蛋白H2A和H2B上，近期虽然已识别出组蛋白H2A的泛素化配基在Hox基因沉默和X染色体失活的H2A泛素化过程中起到了关键作用，但是H2A去泛素化（deubiquitination）过程中的酶以及H2A去泛素化作用至今并不清楚。

在这篇文章中，研究人员报道了组蛋白H2A，Ubp-M（也称为USP16）主要泛素化的功能性特征，实验表明体外Ubp-M接近于核小体底物，与组蛋白H2A去泛素化特异性相关，但是体外与体内都与H2B无关。

值得注意的是，研究人员敲除了HeLa细胞中的Ubp-M，结果发现细胞周期的有丝分裂过程受到影响，导致细胞生长缓慢，进一步研究则揭示Ubp-M引起的H2A去泛素过程是接下来的H3上Ser10的磷酸化，以及细胞进入有丝分裂过程中染色体分离（chromosome segregation）的必要条件。

而且研究人员也证实Ubp-M可以通过H2A去泛素化调控Hox基因表达，阻断Ubp-M的功能会导致光滑爪蟾（Xenopus laevis）的生长缺陷。这些研究识别出了组蛋白H2A的主要去泛素化过程，也证明H2A去泛素化是细胞周期过程和基因表达的关键步骤。

组蛋白修饰

H3·H4 的乙酰化可打开一个开放的染色质结构, 增加基因的表达。转录共同激活物如CBPöP 300、PCA F 实质上是体内的组蛋白乙酰基转移酶(HA T)。相反, HDAC 参与组成转录共同抑制复合物, 已发现的两个共同抑制复合物S IN 3、M i22NHRD(核小体重塑蛋白去乙酰基酶) 都含有HDAC1、HDAC2。S IN 3 的组成为核心(HDAC1、HDAC2、RBA P46öRBA P48 ) + S IN 3AöS IN 3B、SA P30öSA P18共同构成。S IN 3 复合物通过组分S IN 3A 与序列特异性转录因子或共同抑制物包括mael2max, 核激素受体N 2CORöSMRT、甲基化CPG 粘附蛋白(N ECP2、MBD2)相互作用。M i22NHRD 由核心(HDAC1、HDAC2、RBA P46öRBA P48) + M i2、M TA 1öM TA 2、MBD3 组成, 其中MBD3 含有MBD 样序列, 与甲基化DNA 有低亲和力, 分析发现MBD3 与甲基化有关的氨基酸被置换, 由此推测MBD3 与MBD2 相互作用而使M i22NURD 与甲基化DNA 结合。由此看出, DNA 甲基化和组蛋白去乙酰化协同作用共同参与转录阻遏。此外,M i22NURD 还有染色质重塑活性, 所以S IN 3 和M i22 NURD 可能分别在长期和短期转录阻遏调节中起作用。
（生物通：张迪）

原文摘要：
Nature advance online publication 3 October 2007 |
doi:10.1038/nature06256; Published online 3 October 2007
Regulation of cell cycle progression and gene expression by H2A deubiquitination
『Abstract』

附：
Hengbin Wang, Ph.D., Assistant Professor
Address: Kaul Human Genetics Building
Room 402A
720 South 20th Street
Birmingham, AL 35294-0024
E-Mail:[e-mail] [e-mail]

BIOGRAPHY
Dr. Hengbin Wang (b.1969) is an Assistant Professor of Biochemistry and Molecular Genetics. Dr. Wang received his B.S. degree from Hebei Normal University (1991) and Ph.D. degree from China Agricultural University (1997) in China. He began his first postdoctoral training in Kyushu University, Japan. Then he moved to the University of North Carolina at Chapel Hill, joining Dr. Yi Zhang’s laboratory to study the roles of histone modifications in regulating chromatin functions. He joined UAB in 2004.

LAB RESEARCH FOCUS: Regulation of Chromatin Functions by Histone Modifications
In eukaryotic cells, DNA is packaged with histones to form chromatin. Once thought merely as a static structure for DNA compaction, chromatin has now been recognized as being highly dynamic and plays vital regulatory roles in almost all nuclear processes including transcription, replication, repair, recombination, and chromosome segregation. Research during the last ten years revealed that two kinds of activities contribute to chromatin fluidity. One is ATP-dependent nucleosome remodeling; the other is covalent modifications of histone tails. Our lab is particularly interested in how covalent modifications of histone tails regulates chromatin function.

Mostly on its N- and C- terminal tails, histones can be covalently modified by acetylation, phosphorylation, methylation, ubiquitination and ADP-ribosylation. Different modifications control different physiological processes. Acetylation plays fundamental roles in transcription regulation. Methylation, depending on the methylation sites and status, modulates a variety of biological processes including transcription, heterochromatin formation, DNA methylation, Gene imprinting, and X chromosome inactivation. The role of histone ubiquitination has just been revealed. We have been focusing our research on two of those modifications: methylation and ubiquitination.

We will take a series of steps to elucidate the functions of these modifications. First, we will identify novel enzymes responsible for those modifications; second, we will explore functions of those modifications on chromatin-based processes such as transcription; finally we will try to understand the mechanism of those modifications on transcription and further investigate the biological consequences of these modifications. Our long-term goal is to apply this basic research for human diseases.

When I was a postdoc in Dr. Yi Zhang’s lab, my colleagues and I used unique biochemical approaches to address these questions. We have successfully identified six novel HMTases (PRMT1, SET7, SET8, ESET, EZH2, and hDOT1), and more recently, one histone H2A ubiquitin ligase (hPRC1L). I will continue to investigate the biological roles of these enzymes in vivo to gain a better understanding of how the deregulation of these enzymes relates to dysfunction of cell proliferation and human diseases such as cancer. Our preliminary studies show that several of these HMTases play important roles in cancer development.