Regulation of transcriptional consistency by broad H3K4me3 domains in young cells and during aging

 描述（由申请人提供）：我的首要目标是了解衰老的表观基因组调控。器官和组织的功能衰退是衰老的标志，伴随着基因表达水平的变化和细胞类型中的染色质修饰。然而，这些变化对老龄化的影响在很大程度上仍不清楚。最近的研究表明，衰老导致转录网络完整性的丧失，并可能与转录变异性（或“细胞间噪音”）的变化有关。转录调控 变异性对细胞命运决定、胚胎模式和应激反应具有重要影响，但其通过染色质的调节和在衰老中的作用仍然是难以捉摸的。我们最近发现了一种新型的染色质结构域，由H3 K4 me 3修饰标记的宽结构域，其优先标记对细胞身份/功能重要的基因。这些宽的H3 K4 me 3结构域确实预测了高基因表达，但增加了转录一致性（即低变异性）。有趣的是，我们的初步分析表明，广泛的H3 K4 me 3结构域可以在老化过程中被异常修饰。鉴于转录精度随年龄的损失，H3 K4 me 3宽度的调节可能是一种机制，通过该机制，尽管环境波动，仍能确保一致的基因表达。基因表达的这种一致性对于维持细胞和组织在整个生命过程中的稳态可能特别重要。然而，涉及广泛的H3 K4 me 3结构域沉积的机制以及它们如何调节年轻细胞与老年细胞中的转录一致性仍然是未知的。 我提议的目的是 探索这种染色质签名对转录一致性的作用模式及其随年龄的失调。具体而言，我假设广泛的H3 K4 me 3域的沉积是由谱系特异性转录因子和转录的一般调节因子指导的，并且它们促进标记基因的转录一致性，这是一个在衰老过程中受到损害的过程。 我的实验将使用成人神经前体细胞作为模型系统。这些再生细胞可以产生对某些形式的学习和记忆很重要的新神经元，但在衰老过程中会下降。该项目结合使用表观基因组学、细胞生物学和创新计算建模，将i）表征H3 K4 me 3宽度的调节，ii）梳理H3 K4 me 3宽度和转录一致性之间的联系，以及iii）研究H3 K4 me 3结构域的异常重塑随着年龄的增长。最终，这项工作将深入了解衰老的表观遗传调控，并为衰老细胞恢复到年轻的健康状态奠定基础。最后，本提案的职业发展和培训部分将为我成功过渡到独立职业生涯提供关键要素，并使我能够将衰老领域的知识与尖端的实验和计算策略相结合，以提高对衰老过程中受损的一般机制的理解。

 DESCRIPTION (provided by applicant): My overarching goal is to understand the epigenomic regulation of aging. Functional decline of organs and tissues is a hallmark of aging, which is accompanied by changes in gene expression levels and chromatin modifications across cell types. However, the impact of these changes on aging is still largely unclear. Recent work suggests that aging results in a loss of transcriptional networks integrity and may be linked to changes in transcriptional variability (or "cell-to-cell noise"). The regulation of transcriptional variability has important consequences on cell-fate decisions, embryo patterning and stress response, but its regulation by chromatin and role in aging have remained elusive. We have recently identified a new type of chromatin domain, broad domains marked by the H3K4me3 modification, which preferentially mark genes important for cell identity/function. These broad H3K4me3 domains do predict high gene expression but increased transcriptional consistency (i.e. low variability). Interestingly, our pilot analyses suggest that broad H3K4me3 domains can be aberrantly modified during aging. Given the loss of transcriptional precision with age, regulation of H3K4me3 breadth may be a mechanism by which consistent gene expression is ensured despite environmental fluctuations. Such consistency in gene expression may be particularly important to maintain cell and tissue homeostasis throughout life. However, the mechanisms involved in broad H3K4me3 domains deposition and how they regulate transcriptional consistency in young vs. old cells is still unknown. The goal of my proposal is to explore the mode of action of this chromatin signature on transcriptional consistency and its dysregulation with age. Specifically, I hypothesize that the deposition of broad H3K4me3 domains is directed by lineage-specific transcription factors and general regulators of transcription, and that they promote transcriptional consistency of marked genes, a process compromised during aging. My experiments will use adult neural progenitor cells as a model system. These regenerative cells can produce new neurons important for certain forms of learning and memory, but decline during aging. Using a combination of epigenomics, cell biology and innovative computational modeling, this project will i) characterize the regulation of H3K4me3 breadth, ii) tease apart the link between H3K4me3 breadth and transcriptional consistency, and iii) investigate aberrant remodeling of H3K4me3 domains with age. Ultimately, this work will give insights into the epigenetic regulation of aging and lay the groundwork for rejuvenation of aged cells back to a youthful healthy state. Finally, the career development and training components of this proposal will provide key elements for my successful transition to an independent career and my ability to integrate knowledge of the aging field with cutting-edge experimental and computational strategies to improve the understanding of general mechanisms that are compromised during aging.