Defining the mechanisms of epigenetic information flow

定义表观遗传信息流的机制

• 批准号: 10700867
• 负责人: Alexander Jackson Ruthenburg
• 金额: $ 39.76万
• 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/10700867
• 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; 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，蛋白质、DNA 和 RNA 的组合，代表生理学 真核基因组的形式，施加百万倍的长度尺度压缩以适应 细胞核中的DNA。染色质结构不仅仅是静态包装 作为潜在 DNA 功能的动态调节器。局部染色质结构可能 可以稳定数十年，但具有足够的动态来响应信号通路， 增强发育、疾病和疾病中的转录程序变化 环境变化。事实上，细胞身份及其变化是密切相关的。 与染色质状态相关——保持神经元是神经元而不是肝细胞。公寓 来自 DNA 序列特异性转录因子，负责信息载体 对于这种结构变异，是对基因组本身的化学修饰以及随之而来的 参与包装的组蛋白（通常称为“表观遗传”标记），以及 作为作用于染色质界面的非编码RNA。虽然对这些知之甚少 表观遗传信息载体，很明显它们在发育中发挥着至关重要的作用， 认知与疾病。阐明表观遗传的分子机制 信息载体影响染色质结构和功能，特别是在环境中 转录激活的研究是鲁滕堡实验室的统一主题。在接下来的四 几年后，我们将发现并描述新表观遗传的详细机制 信息载体，重点关注核小体水平变异和孤儿组蛋白 修饰，定义最近赞赏的 DNA 修饰的结合伙伴，以及 它们的功能，并对一类进行详细的机械表征 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，我们将从生化角度定义RNA的功能 MLL/SET1 组蛋白修饰复合物家族及其功能 细胞环境中的后果。我们在这些领域的跨学科工作将需要 新工具和实验方法的开发——我们的杰出领域 利用 NIGMS 资助进行开创性工具开发的记录表明，未来 努力也会取得类似的成功。基本机制的理解 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。