Epigenetic mechanisms of regulation of histone lysine methyltransferases involved in leukemia

染色质构象是参与转录，复制， 重组和修复。许多染色质调节机制确保了RNA等酶 聚合酶II能够进入并有效地转录染色质。染色质调节的机制之一 是基于组蛋白的翻译后修饰。化学基团的沉积、读取和去除， 调节染色质结构的特定酶家族。这些修改很少单独起作用， 它们之间经常存在串扰，导致协调的转录输出。其中一项主要 这种串扰的例子见于转录延伸，其中组蛋白H3和H4被乙酰化，H2B 组蛋白H3在赖氨酸4和79处被甲基化（H3K4和H3K79）。COMPASS/MLL和Dot1 是分别催化H3K4和H3K79甲基化的酶，并且在进化上是保守的。 它们在转录延伸、细胞周期控制和DNA修复等过程中发挥重要作用。 在酵母和哺乳动物中发现了同源物。Dot1L和MLL1的失调，已被发现 在几种癌症中，特别是在白血病中，Dot1L和MLL1抑制已经成为一种有希望的 治疗策略锥虫Dot1参与逃避人类免疫系统， 非洲昏睡病等毁灭性疾病。了解Dot1的基本机制， COMPASS/MLL1功能对于发现新的策略来对抗与其相关的疾病至关重要。 放松管制。该提案的重点是发现和表征Dot 1的新机制， COMPASS/MLL1调节。我们将使用生物化学、生物物理和结构方法来研究这些组蛋白 甲基转移酶我们将在细胞和体内验证我们的机制假设。利用这种综合 结构和功能方法以及不同的模型系统将使我们能够从进化上确定 Dot 1和COMPASS/MLL1的保守和生物体特异性生物学功能和调节模式 其可应用于多种疾病的治疗策略。

Chromatin conformation underlies accessibility of enzymes that participate in transcription, replication, recombination, and repair. Many chromatin-regulatory mechanisms ensure that enzymes such as RNA polymerase II gain access to and efficiently transcribe chromatin. One of the mechanisms of chromatin regulation is based on the posttranslational modification of histones. Chemical groups are deposited, read and removed by specific families of enzymes to regulate chromatin structure. These modifications rarely function in isolation, and there is often crosstalk between them that results in a coordinated transcriptional output. One of the prime examples of such crosstalk is seen in transcription elongation, in which histones H3 and H4 are acetylated, H2B is ubiquitinated, and histone H3 is methylated at lysine 4 and 79 (H3K4 and H3K79). COMPASS/MLL and Dot1 are the enzymes that catalyze methylation of H3K4 and H3K79 respectively and are evolutionarily conserved. They play essential roles in processes such as transcription elongation, cell cycle control, and DNA repair. Homologs are found, among others, in yeast, and mammals. Deregulation of Dot1L and MLL1, has been found in several cancers, especially in leukemias, and Dot1L and MLL1 inhibition has emerged as a promising therapeutic strategy. Trypanosome Dot1 is involved in evasion of the human immune system contributing to devastating diseases such as African sleeping sickness. Understanding the mechanisms underlying Dot1 and COMPASS/MLL1 functions is critical to discovery of novel strategies to fight diseases associated with their deregulation. This proposal centers on finding and characterizing novel mechanisms of Dot1 and COMPASS/MLL1 regulation. We will use biochemical, biophysical and structural methods to study these histone methyltransferases. We will validate our mechanistic hypotheses in cells and in vivo. Using this integrative structural and functional approach and different model systems will allow us to determine evolutionarily conserved and organism-specific biological functions and modes of regulation of Dot1 and COMPASS/MLL1 which can be applied to therapeutic strategies for a variety of diseases.