Genomic and Translational Approaches to Neuroendocrine Switching Events

在过去的五年里，这一荣誉奖使我们能够专注于分子“表观基因组学”。 联合调节基因转录程序的策略。这些措施包括识别新的 表观遗传调控；定义活性增强剂的签名；以及提供证据证明增强剂 配基核受体的调节作用本身就是转录单位，转录 具有重要功能的eRNAs。我们还发现了新的组蛋白修饰，并阐明了它们的 生物学功能，并有助于不断增长的证据动态三维 特定基因组区域的相互作用/重组。最后，我们已经提供了初步证据 LncRNAs可以通过变构修饰蛋白的功能来发挥其生物学功能 RNA结合蛋白，以及视黄酸受体对Pol III依赖的Alu重复转录的调节 单位及其在生物过程中的作用。具体贡献包括：阐明PHF8的作用， PHF2和SMYD5在转录调控中的作用；识别LSD1的组织特异性剪接变体的作用； 发现了一种新的H_2A酪氨酸磷酸化，并证明了JMJD6去甲基酶作为一种 通过对特定促进剂采取行动来调节暂停-释放。我们鉴定了E2调节的增强子 程序和配体依赖的Erna转录增加作为功能增强子的标志。 我们确定了MegaTrans复合体和凝聚素I和II对这些功能的招募 增强剂。使用Pit1作为模型，我们还演示了对依赖于Pit1的增强子的需求 与富含Matrin3的网络相互作用有效激活同源结构域依赖的转录 内分泌系统中的程序。我们建议通过探索角色来继续我们在这一扩展中的工作 核受体在调节负的和正的增强子依赖的转录中的作用 计划，定义JMJD6在这些计划中的角色，以及修改后的远程交互在 决定了受调控转录反应背后的染色体变化。我们将使用基因 超增强子调控内分泌发育机制的研究进展 内分泌系统中的程序。 相关性(请参阅说明)： 在这个优秀奖下，我们为理解增强子依赖策略做出了贡献 调控广泛的基因转录程序。我们将继续并扩大这些研究的可取之处 通过研究全球增强子相互作用网络延长时间；负性以及 阳性的基因转录调控程序；以及阐明组件的发育作用 内分泌系统中超增强剂中的增强剂。

During the past five year period, this Merit Award has permitted us to focus on molecular “epigenomic” strategies that combinatorially regulate programs of gene transcription. These include identifying new epigenetic regulators; defining signatures of active enhancers; and providing evidence that enhancers mediating actions of liganded nuclear receptors are themselves regulated transcription units, transcribing functionally important eRNAs. We have also identified new histone modifications and elucidated their biological functions, and contributed to the growing evidence for dynamic three-dimensional interaction/reorganization of specific genomic regions. Finally, we have provided initial evidence that lncRNAs could exert their biological functions based on their actions to allosterically modify functions of RNA-binding proteins, and of retinoic acid receptor regulation of Pol III-dependent Alu repeat transcription units and their roles in biological processes. Specific contributions include: elucidating the roles of PHF8, PHF2 and SMYD5 in transcriptional regulation; identifying roles of a tissue-specific splice variant of LSD1; finding a novel tyrosine phosphorylation of H2A and; demonstrating the role of JMJD6 demethylase as a regulator of pause-release by actions on specific enhancers. We characterized the E2-regulated enhancer program and the ligand-dependent increase in eRNA transcription as a signature of functional enhancers. We identified the recruitment of the MegaTrans complex and Condensins I and II to these functional enhancers. Using Pit1 as a model, we also demonstrated the requirement for Pit1-dependent enhancer interactions with the Matrin3-rich network for effective activation of homeodomain-dependent transcriptional programs in the endocrine system. We propose to continue our work in this extension by exploring the roles of nuclear receptors in regulating negative, as well as positive, enhancer-dependent transcriptional programs, defining the roles of JMJD6 in these programs, and roles of modified long-distance interactions in dictating the chromosomal alterations underlying regulated transcriptional response. We will use genetic approaches to elucidate the mechanisms of super-enhancer regulation of endocrine developmental programs in the endocrine system. RELEVANCE (See instructions): Under this MERIT Award, we have contributed to understanding the enhancer-dependent strategies regulating broad gene transcriptional programs. We will continue and extend these studies in the MERIT Extension period by investigating global enhancer interaction networks; mechanisms of negative as well as positive gene transcriptional regulatory programs; and elucidating developmental roles of component enhancers in superenhancers in the endocrine system.