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，不可能拟合一百万倍长度的压实 核中的DNA。而不是仅用静态包装，而是染色质结构 充当基础DNA功能的动态调节剂。局部染色质结构可能 保持稳定数十年，但足够动态以响应信号通路， 增强转录计划的发展，疾病和 环境变化。确实，蜂窝身份及其变化密切 连接到染色质状态 - 保持神经元而不是肝细胞。除外 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，是对基因组本身的化学修改和随之而来的 涉及包装的Hisstone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。虽然对这些鲜为人知 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。阐明表观遗传学的分子机制 信息载体会影响染色质结构和功能，尤其是在上下文中 转录激活是Ruthenburg实验室的统一主题。在接下来的四个 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异和孤立的组蛋白 修改，定义结合伙伴的最近理解的DNA修饰和 它们的功能，并执行一类的详细机械表征 我们发现的分子 - 富含染色质的非编码RNA，充当局部 转录激活剂。此外，我们将在生化上定义RNA的功能 MLL/SET1组蛋白修饰复合物及其功能 在细胞环境中的后果。我们在这些领域的跨学科工作将需要 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 努力将取得类似的成功。对 我们将通过这些途径开发的表观遗传信息系统将影响我们的 了解核功能及其在疾病中的失调。