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2001年，David Allis博士提出，DNA包装中的微小化学修饰可能会形成影响基因表达的密码。从那时起，人们一直在努力了解这些不同的修饰有什么作用，以及它们是如何影响生物体的生物学的。以前，我的实验室在蠕虫中提供的证据表明，随着细胞自我复制，这些修饰可以稳定地从一个细胞遗传到另一个细胞。这些实验将确定当哺乳动物的基因从父母传给后代时，这些信息会发生什么。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，这项工作有可能揭示从出生缺陷到自闭症等一系列疾病的原因。所有实验都将与附近奥格尔索普大学的本科生合作，在奥格尔索普教授凯伦·舒梅切尔博士的指导下进行。这些学生中有许多是少数民族和/或他们家族中第一个上大学的人，他们无法使用卓越的人类模型老鼠进行研究。因此，为这些学生提供参与这项研究的机会有可能深刻地影响他们对科学和科学研究的理解。技术描述多细胞生物体存在的两个最基本的部分是(1)细胞维持其细胞命运的能力，以及(2)细胞如何在关键的发育转变过程中经历细胞命运的变化。要做到这一点，细胞必须能够(A)通过有丝分裂忠实地传递基因表达模式，以及(B)在发育过渡期间改变转录模式。然而，控制这些过程的机制目前尚不清楚。为了研究这些机制，我们将使用组蛋白去甲基酶LSD1/KDM1A的小鼠模型来确定该酶在(1)配子到胚胎的转变和(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作为哺乳动物的转录记忆功能，(B)研究组蛋白甲基化和DNA甲基化之间的关系，以及(C)确定LSD1在调节细胞命运中的功能。通过在我们理解组蛋白甲基化如何发挥维持细胞命运的作用以及在细胞命运转变期间如何调控组蛋白甲基化方面提供了潜在的范式转变，这项工作有可能极大地影响我们对从出生缺陷到自闭症等广泛疾病的理解和治疗。