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

年轻细胞和衰老过程中广泛的 H3K4me3 结构域对转录一致性的调节

• 批准号: 9755277
• 负责人: Berenice Anath Benayoun
• 金额: $ 23.32万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755277
• 关键词: Adult; Affect; Age; Aging; B-Lymphocytes; Back; Binding; Biological Assay; Biological Models; Cell model; Cells; Cellular biology; Chemicals; Chromatin; Complex; Computer Simulation; Data; Data Set; Deposition; Disease; Elements; Embryo; Ensure; Environment; Event; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Goals; Histone H3; Homeostasis; Impairment; Knowledge; Learning; Life; Link; Longevity; Lysine; Maintenance; Memory; Memory Loss; Meta-Analysis; Modeling; Modification; Molecular; Mus; Neurons; Noise; Organ; Pattern; Polymerase; Predictive Factor; Process; RNA; RNA Polymerase II; Regulation; Rejuvenation; Role; Sampling; Stress; Testing; Tissues; Training; Transcriptional Regulation; Validation; Work; age related; base; biological adaptation to stress; career; career development; cell age; cell type; chromatin modification; epigenetic regulation; epigenomics; experimental study; functional decline; gene function; genome-wide; genomic data; healthspan; improved; in vivo; inhibitor/antagonist; innovation; insight; interest; knock-down; member; nerve stem cell; novel; predictive signature; prevent; public health relevance; regenerative; response; single molecule; small hairpin RNA; transcription factor; transcriptome sequencing

 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.

 描述(由申请者提供)：我的首要目标是了解衰老的表观遗传规律。器官和组织的功能衰退是衰老的一个标志，伴随着不同类型细胞的基因表达水平和染色质修饰的变化。然而，这些变化对衰老的影响在很大程度上仍然不清楚。最近的研究表明，衰老会导致转录网络完整性的丧失，并可能与转录可变性(或“细胞间噪声”)的变化有关。转录调控 可变性对细胞命运决定、胚胎模式和应激反应有重要影响，但它由染色质调节和在衰老中的作用仍然难以捉摸。我们最近发现了一种新的染色质结构域，以H3K4me3修饰为标志的广泛结构域，它优先标记对细胞身份/功能重要的基因。这些广泛的H3K4me3结构域确实预示着基因的高表达，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H3K4me3结构域可以在老化过程中发生异常修改。鉴于随着年龄的增长，转录精确度会下降，调节H3K4me3的宽度可能是一种机制，通过这种机制，尽管环境波动，仍能确保一致的基因表达。这种基因表达的一致性可能对维持细胞和组织在整个生命过程中的动态平衡特别重要。然而，涉及广泛的H3K4me3结构域沉积的机制以及它们如何调节年轻细胞和老年细胞的转录一致性仍不清楚。我的提议的目的是 探索该染色质信号对转录一致性的作用方式及其随年龄的失调。具体地说，我假设广泛的H3K4me3结构域的沉积是由谱系特异的转录因子和一般转录调节因子指导的，它们促进了标记基因的转录一致性，这一过程在衰老过程中受到了影响。我的实验将以成年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至关重要的新神经元，但在衰老过程中会衰退。利用表观基因组学、细胞生物学和创新的计算模型，该项目将i)表征H3K4me3宽度的调节，ii)梳理H3K4me3宽度与转录一致性之间的联系，iii)研究H3K4me3结构域随年龄的异常重塑。最终，这项工作将深入了解衰老的表观遗传调控，并为衰老细胞恢复年轻健康状态奠定基础。最后，这项提案的职业发展和培训部分将为我成功过渡到独立的职业生涯提供关键要素，并提供我将老龄化领域的知识与尖端实验和计算策略相结合的能力，以提高对老龄化过程中受到损害的一般机制的理解。

项目成果

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.

• DOI: 10.1016/j.cmet.2018.06.008
• 发表时间: 2018-09-04
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Kim KH;Son JM;Benayoun BA;Lee C
• 通讯作者: Lee C

Measuring Phagocytosis in Bone Marrow-Derived Macrophages and Peritoneal Macrophages with Aging.

• DOI: 10.1007/978-1-0716-0592-9_14
• 发表时间: 2020
• 期刊: Methods in molecular biology
• 作者: Ryan Lu;N. Sampathkumar;B. Benayoun

Special issue on "Molecular genetics of aging and longevity": a critical time in the field of geroscience.

“衰老与长寿的分子遗传学”特刊：老年科学领域的关键时刻。

• DOI: 10.1007/s00439-020-02125-7
• 发表时间: 2020
• 期刊: Human genetics
• 影响因子: 5.3
• 作者: Benayoun,BéréniceA;Veitia,ReinerA
• 通讯作者: Veitia,ReinerA

Sex-dimorphism in aging: are we missing half of the picture?

衰老过程中的性别二态性：我们是否错过了一半？

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Benayoun,BéréniceA;Lu,RyanJ;Kim,Minhoo;McGill,CassandraJ
• 通讯作者: McGill,CassandraJ

The microbiome: an emerging key player in aging and longevity.

• DOI: 10.1016/j.tma.2020.07.004
• 发表时间: 2020
• 期刊: Translational medicine of aging
• 作者: Minhoo Kim;B. Benayoun