窦亚丽Cell子刊发现新调控模式

　　

生物通报道：来自密歇根大学，普林斯顿大学的研究人员发表了题为“ASH2L Regulates Ubiquitylation Signaling to MLL: trans-Regulation of H3 K4 Methylation in Higher Eukaryotes”的文章，发现了一种新型调控模式：高等真核生物H3K4甲基化的反式调控（trans-Regulation），这将扩展泛素信号通路对染色质调控的范围。相关研究成果公布在Molecular Cell杂志上。

文章的通讯作者是密歇根大学的窦亚丽（Yali Dou, Ph.D.）博士，其早年毕业于北京大学医学院（Peking University Health Center），主要研究方向为表观遗传学，组蛋白质组学方面（生物通专访文章：窦亚丽：直击干细胞表观遗传调控 ）。

真核生物染色质的组蛋白末端会发生多种化学修饰（包括乙酰化和甲基化修饰等），是真核生物细胞随环境变化而改变基因表达谱式的重要调控方式。之前的研究发现组蛋白H3K4甲基化分布于基因的启动子区，对基因转录主要起正调控作用，并且H2B泛素化（H2Bub）和H3K4甲基化之间的串扰（crosstalk），也在转录激活过程中各种辅助因子的协同作用方面扮演了重要的角色。

然而在高等真核生物中，对于这种反式修饰信号途径（trans-tail signaling pathway，生物通译）的分子机理了解的很少，为此，在这篇文章中，研究人员展开了深入探讨，发现MLL复合物中的ASH2L是这种H2Bub依赖性H3K4甲基化作用的必需元素，而且如果删除，或者沉默ASH2L的N末端一种螺旋结构域，也会导致这种修饰调控作用无法进行。

此外，研究人员还发现这两种修饰方式之间的交流并不需要核小体或者组蛋白的泛素化，就能发挥作用，同时这种调控能促进三种甲基化状态下MLL的活性，不过一种MLL的同源异构体：MLL3并不会对H2Bub作出应答，这表明MLL家族组蛋白甲基化转移酶存在调控特异性。

这些研究指出，从典型的组蛋白串扰发展到非组蛋白，这将扩展泛素信号通路对染色质调控的范围。

窦亚丽研究组致力于表观遗传学，组蛋白质组学方面的研究，他们曾揭示了一种称作Mof的蛋白在维持干细胞干性方面起至关重要的作用，并启动小鼠中的干细胞转变为了特化细胞。

研究人员发现组蛋白乙酰转移酶Mof在维持ESC自我更新和多能性中发挥了至关重要的作用。人类MOF隶属于MYST组蛋白乙酰转移酶家族，是人体内催化H4K16乙酰化的主要的组蛋白乙酰转移酶，在早期胚胎发育、DNA损伤修复和癌症发生等过程中发挥非常关键的作用。

窦亚丽博士多年来从事Mof研究，对于Mof在干细胞生物学中的错综复杂性感到困惑不解，他们为了解开这个酶的关键作用，分析了当DNA缠绕组蛋白时往DNA上添加临时标签的因子，结果发现Mof缺失ESCs失去了特征性形态、碱性磷酸酶（AP）染色和分化潜能。这些细胞的核心转录因子Nanog、Oct4和Sox2显示异常表达。值得注意的是，研究人员发现当Nanog过表达时可部分抑制无Mof 的ESCs表型，表明在ESCs 中Mof在功能上充当了Nanog 的上游调控因子。（生物通：万纹）

原文摘要：

ASH2L Regulates Ubiquitylation Signaling to MLL: trans-Regulation of H3 K4 Methylation in Higher Eukaryotes

Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.

作者简介：
窦亚丽简介
B.S.：北京大学
Ph.D.：罗切斯特大学
Postdoctoral：洛克菲勒大学
研究领域：

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 ubiquitylation. Through histone modifications, chromatin modification enzymes act either synergistically or antagonistically in regulating transcription, cell cycle progression, DNA damage repair, and DNA replication. Given the fundamental roles of histone modifications in organizing chromatin and maintaining proper gene functions, it is not surprising that mutations in chromatin modifying enzymes are often found in human diseases.

Our broad objectives are to understand the epigenetic regulation of various cellular processes through chromatin modifying enzymes. 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 leukemia, a thorough understanding of the mechanism for its action and regulation allows us to develop specific inhibitors as novel chemotherapeutic agents.

荣誉：
2012 Leukemia & Lymphoma Society Scholar Award
2011 Stand Up to Cancer IRG Award
2010 AACR Gertrude B. Elion Cancer Research Award
2010 American Cancer Society RSG Award
2007 Biomedical Science Scholar, University of Michigan
2004-2007 The Irvington Institute for Immunological Research Fellowship