Defining the mechanisms of epigenetic information flow

定义表观遗传信息流的机制

• 批准号: 10406734
• 负责人: Alexander Jackson Ruthenburg
• 金额: $ 41.1万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406734
• 关键词: Area; Binding; Biochemical; Biochemistry; Biology; Biophysics; Cell Nucleus; Cellular biology; Chemicals; Chromatin; Chromatin Structure; Cognition; Complex; DNA; DNA Modification Process; DNA Sequence; Development; Discipline; Disease; Epigenetic Process; Family; Funding; Future; Genetic Transcription; Genome; Genomics; Goals; Hepatocyte; Histones; Information Systems; Length; Modification; Molecular; National Institute of General Medical Sciences; Neurons; Nuclear; Nucleosomes; Orphan; Physiological; Play; Proteins; RNA; Research; Role; Signal Pathway; Signal Transduction; Transcription Coactivator; Transcriptional Activation; Untranslated RNA; Variant; Work; environmental change; histone modification; programs; success; technology development; tool; tool development; transcription factor

Chromatin, the assemblage of protein, DNA and RNA that represents the physiologic form of the eukaryotic genome, imposes a million-fold length-scale compaction to fit DNA in the nucleus. Rather than serving as mere static packaging, chromatin structure acts as a dynamic regulator of underlying DNA function. Local chromatin structure may be stable for decades, yet is sufficiently dynamic to respond to signaling pathways, potentiating transcriptional program changes in development, disease, and environmental changes. Indeed, cellular identity and changes thereof are intimately connected to chromatin states-- keeping a neuron a neuron and not a liver cell. Apart from DNA sequence-specific transcription factors, the information carriers responsible for this structural variation are chemical modifications to the genome itself and attendant histone proteins involved in packaging (often referred to as “epigenetic” marks), as well as noncoding RNA acting at the chromatin interface. Although little known about these epigenetic information carriers, it is clear that they play crucial roles in development, cognition and disease. Elucidation of the molecular mechanisms by which epigenetic information carriers impact chromatin structure and function, particularly in the context of transcriptional activation is the unifying theme of the Ruthenburg lab. In the next four years, we will discover and characterize the detailed mechanisms of new epigenetic information carriers, focusing on nucleosome-level variation and orphaned histone modifications, defining binding partners for recently appreciated DNA modifications and their function, and performing detailed mechanistic characterization of a class of molecules we discovered--chromatin-enriched noncoding RNA that act as local transcriptional activators. In addition, we will biochemically define the function of RNA in the MLL/SET1 family of histone modification complexes and its functional consequences in cellular contexts. Our interdisciplinary work in these areas will require the development of new tools and experimental approaches—our outstanding track record of pioneering tool development with NIGMS funding makes the case that future efforts will meet with similar success. The fundamental mechanistic understanding of epigenetic information systems we will develop through these avenues will impact our understanding of nuclear function and its dysregulation in disease.

染色质，代表生理学的蛋白质，DNA和RNA的组合 真核基因组的形式，施加了一百万倍长度的压实 核中的DNA，而不是仅用作静态包装的染色质结构 多像多克斯多像到一定程度的程度高达一定程度的人 保持稳定数十年，但对信号通路的响应足够动态， 增强转录计划的发展，疾病和 环境变化。 连接到染色质 - 保持神经元而不是肝细胞 从DNA序列特异性转录因子中，信息载体负责 对于这种结构变化，是对基因组和伴随的化学修饰 包装涉及的组蛋白蛋白（通常称为“表观遗传学”标记） 作为在染色质界面作用的非编码RNA。 表观遗传信息载体，很明显，它们在开发中扮演着关键的角色， 认知和疾病。 信息Carromatin蛋白蛋白结构和功能，尤其是在上下文中 转录激活是接下来的四个实验室的统一。 几年，我们将发现并描述新表观遗传学的详细机制 信息载体，重点是核小体级别的变化和甲骨一体的组蛋白 修改，为最近理解的DNA修改和 它们的功能，并执行一类的详细机械表征 我们发现的分子 - 富含染色质蛋白的非编码RNA，作为局部 转录激活剂。 组蛋白修饰复合物ATS功能的MLL/SET1家族功能 我们在这些领域的跨学科工作中的后果 开发新工具和实验方法 - 我们的出色轨道 通过NIGMS资金开发开发工具的记录使得未来 具有相似成功的敌方。 我们将通过当时开发的表观遗传信息系统将影响我们的 了解核功能，是疾病中的失调。