Molecular analysis of ASH1L

项目摘要 人骨髓灰质醇1(缺失的、小的或同源异形的盘状细胞，如1)介导细胞增殖和存活 造血干细胞，通常在白血病中表达上调。它是造血所必需的。 发育基因的发育和表达，包括HOX基因家族。 在混合细胞性白血病(MLL)-重排急性白血病中发现的Ash11活性上调 淋巴母细胞性白血病(ALL)通常与预后不良有关。阿什利是一名少校 甲基化组蛋白H3的甲基转移酶，产生表观遗传标记H3K36me2 与转录激活和延伸有关。Ash1l包含一个独特的组合 催化甲基转移酶SET结构域和相邻的溴结构域(BD)，PHD指， 以及一个生物学功能不明确的BAH结构域。我们最近的研究表明，BD、PHD和 Ash1的Bah结构域是表观遗传阅读器，能够识别组蛋白的不同状态 H3.Ash1这些新功能背后的分子机制尚不清楚，将 在拟议的研究中予以澄清。我们假设，伴随而来的识别不同的 PHD、BD和BAH域的组蛋白状态在启动子上招募或稳定Ash1 Ash1靶基因，对Ash1的催化活性和H3K36的甲基化是必需的 这些基因。我们试图理解BD、PHD和BAH域之间的串扰 并确定了多价键的分子机制和功能意义 Ash11与染色质的结合。我们将在体外和体内使用互补的 建立分子和结构基础并确定生物学重要性的方法 由Ash1读取器结合的组蛋白。这项研究将提供原子分辨率的洞察力 Ash1信号通路可能构成治疗干预和治疗的新靶点 增强我们对表观遗传驱动基因的基本原理的了解 抄写。它还将有助于更好地理解与异常相关的人类癌症 包括急性白血病在内的As11的活动性。

Project Summary Human ASH1L (absent, small, or homeotic discs like 1) mediates proliferation and survival of hematopoietic stem cells and is often upregulated in leukemias. It is required for hematopoietic development and expression of developmental genes, including the HOX gene family. Upregulated activity of ASH1L, found in mixed lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL), is generally associated with a poor prognosis. ASH1L is a major methyltransferase that methylates histone H3, generating the epigenetic mark H3K36me2 associated with transcriptional activation and elongation. ASH1L contains a unique combination of the catalytic methyltransferase SET domain and adjacent bromodomain (BD), a PHD finger, and a BAH domain with unclear biological roles. Our recent studies reveal that the BD, PHD and BAH domains of ASH1L are epigenetic readers capable of recognizing distinctive states of histone H3. The molecular mechanisms underlying these novel functions of ASH1L are unknown and will be elucidated in the proposed studies. We hypothesize that the concomitant recognition of distinct histone states by the PHD, BD and BAH domains recruits or stabilizes ASH1L at promoters of ASH1L target genes and is necessary for the catalytic activity of ASH1L and methylation of H3K36 at these genes. We seek to understand a crosstalk between the BD, PHD and BAH domains of ASH1L and determine the molecular mechanism and functional significance of the multivalent engagement of ASH1L with chromatin. We will employ complementary in vitro and in vivo approaches to establish the molecular and structural basis and define the biological importance of histone binding by ASH1L readers. This research will provide atomic-resolution insights into ASH1L signaling pathways that may constitute new targets for therapeutic interventions and enhance our knowledge of fundamental principles underlying the epigenetic-driven gene transcription. It will also lead to a better understanding of human cancers associated with aberrant activity of ASH1L, including acute leukemias.