Function of MLL in transcription regulation

项目摘要 细胞特性由整合细胞信息的细胞特异性转录电路决定 历史和细胞外线索。它通常涉及染色质水平的多层调控。 表观基因组学研究已经确定了与转录相关的保守染色质特征 激活。其中之一是组蛋白H3 K4甲基化在顺式调节元件上的富集化 包括基因启动子和增强子。这些调控序列通常起着如下作用 具有意想不到的复杂性和动态性的集成转录因子结合平台 在不同的细胞类型中。在哺乳动物中，H3K4甲基化是由混合血统沉积的 白血病(MLL)酶家族。每个MLL都发挥着基本的、非冗余的功能 在胚胎发育过程中。据报道，在许多人类中存在MLL的反复突变 疾病包括发育障碍、癌症和免疫性疾病。然而， 每个MLL的具体职能和监管问题仍然存在。目前也不清楚是否 MLLS的酶活性在转录调控中起着不可缺少的作用。在这里，我们将 研究MLL家族的创始成员MLL1在细胞命运决定中的作用 并使用强大的干细胞分化和重新编程模型进行转化。我们将解剖 包括催化集结构域在内的每个MLL1结构域在细胞命运中的基本功能 决心。我们还将研究MLL1调节转录和 它可能与其他MLL有何不同。我们的研究将为基础研究提供新的见解 多能性的机制和基因调控。

Project Summary Cell identity is determined by cell specific transcription circuitry that integrate information of cell history and extracellular cues. It often involves multilayered regulation at the level of chromatin. Epigenomic studies have identified conserved chromatin features associated with transcription activation. Among them is enrichment of histone H3 K4 methylation at cis-regulatory elements including gene promoters and enhancers. These regulatory sequences often function as integrated transcription factor binding platforms that have unexpected complexity and dynamics in different cell types. In mammal, H3 K4 methylation is deposited by the mixed lineage leukemia (MLL) family of enzymes. Each MLL plays an essential and non-redundant function during embryonic development. Recurrent mutations in MLLs are reported in many human diseases including developmental disorders, cancers and immunological diseases. However, questions of specific function and regulation of each MLL remain. It is also unclear whether the enzymatic activity of MLLs has any obligatory role in transcription regulation. Here we will examine the function of MLL1, the founding member of the MLL family, in cell fate determination and transition using a robust stem cell differentiation and reprograming model. We will dissect the essential function of each MLL1 domain including the catalytic SET domain in cell fate determination. We will also examine the mechanism by which MLL1 regulates transcription and how it may be distinct from other MLLs. Our study will provide novel insights into basic mechanisms of pluripotency and gene regulation.