A novel strategy to identify proteins that interpret histone methylation patterns deposited by Set1 and Set2

一种识别解释 Set1 和 Set2 沉积的组蛋白甲基化模式的蛋白质的新策略

• 批准号: 31128325
• 负责人: Professor Dr. Sigurd Braun
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/31128325?language=en
• 关键词: novel; strategy; identify; proteins; interpret

Regulation of gene expression independent of the DMA sequence is referred to as epigenetic control; it affects the structure and accessibility of chromatin, particularly through histone modifications (e.g., acetylation, methylation). Inappropriate epigenetic regulation plays a key role in tumorigenesis. For example, the human leukemia protooncogenes MIL and NSD1 are mutated in different forms of leukemia, but how they contribute to tumorigenesis is not well understood. Both MLL and NSD1 encode histone methyltransferases, and their yeast orthologs, Set1 and Set2, methylate histone H3 at lysine residues 4 and 36, respectively. Recent data indicated that Set1 and Set2 function in preventing the spreading of silenced chromatin. The intention of this project is to gain new insights into the mechanisms by which Set1 and Set2 antagonize gene silencing. To this end, I will identify downstream effectors of Set1 and Set2, and study their role in anti-silencing. In particular, I will take a novel genome-wide approach using the DamiD technique to identify proteins that are recruited to histones in a manner that is dependent on Set1 or Set2 activity. Identified candidates will be further characterized in vivo by their contribution to prevent the spreading of heterochromatin and in vitro by biochemical binding studies.

独立于DMA序列的基因表达调控被称为表观遗传调控；它影响染色质的结构和可及性，特别是通过组蛋白修饰(例如，乙酰化、甲基化)。不适当的表观遗传调控在肿瘤的发生中起着关键作用。例如，人类白血病原癌基因MIL和NSD1在不同形式的白血病中发生突变，但它们在肿瘤发生中的作用尚不清楚。MLL和NSD1都编码组蛋白甲基转移酶，它们的酵母同源基因Set1和Set2分别编码赖氨酸残基4和36的甲基化组蛋白H3。最近的数据表明，Set1和Set2在阻止沉默的染色质扩散方面发挥了作用。这个项目的目的是对Set1和Set2拮抗基因沉默的机制有新的见解。为此，我将确定Set1和Set2的下游效应子，并研究它们在抗沉默中的作用。特别是，我将采用一种新的全基因组方法，使用DamID技术来识别以依赖于Set1或Set2活性的方式被招募到组蛋白中的蛋白质。已确定的候选者将在体内通过他们对防止异染色质扩散的贡献来进一步表征，并在体外通过生化结合研究来进一步表征。