Function of MLL in transcription regulation

MLL在转录调控中的功能

基本信息

批准号：
9908876
负责人：
Yali Dou
金额：
$ 35.09万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908876
关键词：
3-Dimensional Aging Architecture Binding CCCTC-binding factor Cells Chromatin Cues Data Defect Deposition Development Developmental Therapeutics Program Distal Embryonic Development Enhancers Enzymes Epiblast Epigenetic Process Family Foundations Gene Expression Regulation Genes Genetic Genetic Models Genetic Transcription Genome Goals Histone H3 Histones Human Immune System Diseases In Vitro Infection Inflammation Inner Cell Mass Link MLL gene Malignant - descriptor Malignant Neoplasms Mammalian Cell Mammals Mediating Medicine Methylation Methyltransferase Mixed-Lineage Leukemia Modeling Molecular Mutation Natural regeneration Nucleic Acid Regulatory Sequences Play Post-Translational Protein Processing Process Recording of previous events Recurrence Regenerative Medicine Regulation Regulatory Element Reporting Research Role SET Domain Science Syndrome Testing Totipotent Transcriptional Activation Transcriptional Regulation Work cell type developmental disease embryo stage 2 epigenetic regulation epigenomics extracellular histone methyltransferase histone modification human disease in vivo insight loss of function member novel pluripotency programs promoter small molecule inhibitor stem cell biology stem cell differentiation stem cells transcription factor

项目摘要

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.

项目摘要细胞身份由整合细胞信息的细胞特异性转录电路确定历史和细胞外提示。它通常涉及染色质水平的多层调节。表观基因组研究已经确定了与转录相关的保守染色质特征激活。其中是在顺式调节元件上富集组蛋白H3 K4甲基化包括基因启动子和增强子。这些调节序列通常充当具有意外复杂性和动态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，H3 K4甲基化由混合谱系沉积白血病（MLL）酶家族。每个MLL扮演着必不可少的和非冗余的功能在胚胎开发过程中。在许多人类中报道了MLL中的复发突变包括发育障碍，癌症和免疫疾病在内的疾病。然而，每个MLL的特定功能和调节问题仍然存在。还不清楚是否 MLL的酶活性在转录调节中具有任何强制性作用。我们会在这里检查MLL家族的创始成员MLL1在细胞命运确定中的功能并使用强大的干细胞分化和重编程模型过渡。我们将剖析每个MLL1域的基本功能，包括细胞命运中的催化集域决心。我们还将检查MLL1调节转录和它如何与其他MLL不同。我们的研究将提供对基本的新见解多能性和基因调节的机制。