Defining the mechanisms of epigenetic information flow

染色质，代表生理的蛋白质、DNA和RNA的集合 真核生物基因组的形式，施加了百万倍的长度尺度的压缩来适应 细胞核中的DNA。染色质结构不是单纯的静态包装 作为潜在DNA功能的动态调节器。局部染色质结构可以 在几十年里保持稳定，但又足够有活力来对信号通路做出反应， 增强发育、疾病和基因转录程序的变化 环境变化。事实上，细胞身份及其变化是密切相关的 与染色质状态有关--使神经元成为神经元，而不是肝细胞。分开 从DNA序列特异的转录因子来看，信息载体负责 这种结构变化是对基因组本身及其随之而来的化学修饰 与包装有关的组蛋白(通常被称为“表观遗传”标记) 作为作用于染色质界面的非编码RNA。尽管人们对这些鲜为人知 表观遗传信息载体，显然它们在发育中发挥着关键作用， 认知和疾病。阐明表观遗传学的分子机制 信息载体影响染色质的结构和功能，尤其是在 转录激活是Ruthenburg实验室的统一主题。在接下来的四年里 ，我们将发现并描述新的表观遗传学的详细机制 关注核小体水平变异和孤儿组蛋白的信息载体 修饰，为最近欣赏的DNA修饰定义结合伙伴，以及 它们的功能，并对一类 我们发现的分子--富含染色质的非编码RNA 转录激活剂。此外，我们还将从生物化学的角度定义RNA在 组蛋白修饰复合体MLL/SET1家族及其功能 在蜂窝环境中的后果。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--我们出色的赛道 NIGMS资助的开创性工具开发的记录表明，未来 这些努力也会取得类似的成功。的基本机械论理解 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 对核功能及其在疾病中的失调的理解。

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.