LSD1 reprograms epigenetic memory to enable changes in cell fate

LSD1 重新编程表观遗传记忆以改变细胞命运

• 批准号: 1354998
• 负责人: David Katz
• 金额: $ 81.77万
• 依托单位: Emory University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1354998&HistoricalAwards=false
• 关键词: LSD1; reprograms; epigenetic; memory; enable

Nontechnical explanationIn 2001, Dr. David Allis proposed that small chemical modifications in the packaging of DNA could form a code that affects the expression of genes. Since then, an intense effort has been underway to understand what these different modifications do and how they affect the biology of organisms. Previously my lab provided evidence in worms suggesting that these modifications can be stably inherited from cell to cell as cells replicate themselves. These experiments will determine what happens to this information as genes are passed from parents to offspring in mammals. In addition, this research will determine whether or not the information contained in the packaging of DNA can influence the information encoded in the DNA itself. By understanding these basic biological mechanisms, this work has the potential to shed light on the cause of a broad range of diseases, from birth defects to autism. All of the experiments will be carried out in partnership with undergraduates from the nearby Oglethorpe University, under the guidance of Oglethorpe professor Dr. Karen Schmeichel. These students, many of whom are minorities and/or first in their family to go to college, have no access to research using mice, the preeminent human model. Therefore, providing these students with the opportunity to participate in this research has the potential to profoundly impact their understanding of science and scientific research.Technical descriptionTwo of the most fundamental parts of the existence of multicellular organisms are (1) the ability of cells to maintain their cell fate, and (2) how cells undergo changes in cell fate during key developmental transitions. To accomplish this, cells must be able to (A) faithfully transmit patterns of gene expression through mitosis and (B) change transcriptional patterns during developmental transitions. However, the mechanisms that control these processes are currently unknown. To investigate these mechanisms we will use a mouse model of the histone demethylase LSD1/KDM1a to determine the function of this enzyme during (1) the gamete-to-embryo transition and (2) in testis stem cells. Through these experiments, we will (A) determine whether histone methylation can function as a transcriptional memory in mammals, (B) investigate the relationship between histone methylation and DNA methylation and (C) determine the function of LSD1 in regulating cell fate. By providing a potential paradigm shift in our understanding of how histone methylation functions to maintain cell fates and how this histone methylation is regulated during cell fate transitions, this work has the potential to highly impact our understanding and treatment of a broad spectrum of diseases, from birth defects to autism.

非技术解释在2001年，戴维·艾利斯（David Allis）博士提出，DNA包装中的小化学修饰可能形成影响基因表达的代码。从那时起，就一直在进行强烈的努力，以了解这些不同的修饰的作用以及它们如何影响生物的生物学。以前，我的实验室在蠕虫中提供了证据，表明这些修饰可以稳定地从细胞到细胞复制自身稳定。这些实验将决定该信息会发生什么，因为基因从父母传递到哺乳动物的后代。此外，这项研究将确定DNA包装中包含的信息是否会影响DNA本身编码的信息。通过了解这些基本的生物学机制，这项工作有可能阐明从出生缺陷到自闭症的广泛疾病的原因。在Oglethorpe教授Karen Schmeichel博士的指导下，所有实验将与附近Oglethorpe大学的本科生合作进行。这些学生，其中许多是少数群体和/或首先要上大学的学生，无法使用杰出的人类模型MICE进行研究。因此，为这些学生提供参与这项研究的机会有可能深刻影响他们对科学和科学研究的理解。技术描述是多细胞生物存在的最基本部分的技术描述（1）细胞维持细胞命运的能力，以及（2）细胞在密钥发育过程中细胞在密钥发育过程中如何在细胞中发生变化。为此，细胞必须能够（a）通过有丝分裂忠实地传输基因表达模式，并且（b）在发育过渡期间改变转录模式。但是，目前未知的控制这些过程的机制是未知的。为了研究这些机制，我们将使用组蛋白脱甲基酶LSD1/KDM1A的小鼠模型来确定（1）在（1）配子到 - 晶状体过渡期间和（2）在睾丸干细胞中的功能。通过这些实验，我们将（a）确定组蛋白甲基化是否可以充当哺乳动物中的转录记忆，（b）研究组蛋白甲基化与DNA甲基化之间的关系，（c）确定LSD1在调节细胞命运中的功能。通过提供对组蛋白甲基化如何维持细胞命运以及在细胞命运转变期间如何调节这种组蛋白甲基化的潜在范式转移，这项工作有可能极大地影响我们对从出生缺陷到自闭症的广泛疾病的理解和治疗。