The function of epigenetic memory in cell fate

表观遗传记忆在细胞命运中的作用

• 批准号: 1931697
• 负责人: David Katz
• 金额: $ 120万
• 依托单位: Emory University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1931697&HistoricalAwards=false
• 关键词: function; epigenetic; memory; cell; fate

Within an organism, every different type of cell contains the same set genes, but only a subset of these genes are on. This gives rise to the many different types of cells. Over many years scientists have made progress in understanding how the packaging of genes into an open or closed formation determines whether the gene will be on or off. This is a fundamental part of biology. However, scientists still have very little understanding of what happens when these mechanisms go awry and different cell type programs are competing against one another. The microscopic worm C. elegans has a unique feature where every cell type is made exactly the same way in every embryo. This provides a unique opportunity to address this question. The Katz Lab will take advantage of the invariant embryo in these worms to learn the rules governing how cells respond when an incorrect program is activated alongside the normal program. This will address a fundamental aspect of biology with wide ranging implications for many different and important processes.Using C. elegans, the Katz Lab discovered that the H3K4me2 demethylase, LSD1, acts along with the H3K9 methyltransferase, MET-2, as an epigenetic reprogramming switch, replacing the active histone modification, H3K4me2, with the repressive modification,H3K9me2, at fertilization. In spr-5;met-2 mutants, the inappropriate inheritance of histone methylation leads to the ectopic expression of ∼200 critical germline genes in somatic cells, resulting in developmental delay. This model provides a unique opportunity to understand how inappropriately inherited chromatin affects transcription and how the expression of one developmental program affects cells trying to specify a different developmental program. To address this question, the Katz Lab will take advantage of the invariant C. elegans lineage to determine how chromatin, gene expression and cell fate are affected with single cell resolution in spr-5;met-2 mutants. This project is highly complementary to broader impacts pursued by the Katz Lab. Over the past 5 years of NSF funding, the Katz Lab at Emory University has partnered with a nearby liberal arts college, Oglethorpe University, to establish a Pipeline Course Embedded Undergraduate Research (CURE) curriculum, where biology majors take part in C. elegans research reiteratively throughout the biology major. This culminates in a Capstone Course, led by a postdoctoral fellow from the Katz Lab, where students spend the bulk of their class- time over a semester on an original C. elegans research project related to ongoing experiments in the Katz Lab. Because of the Pipeline CURE, the majority of biology majors now participate in authentic research, and initial surveys indicate that this authentic research can recapitulate the experience that is typically only found in an apprentice style approach at a major research university. To continue to lower the bar of accessibility to authentic research at a liberal arts college, the Katz Lab now proposes to provide every biology major the opportunity to conduct thesis research performed entirely in the classroom at Oglethorpe University.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在一个生物体中，每种不同类型的细胞都含有相同的基因组，但只有这些基因的一个子集是开启的，这就产生了许多不同类型的细胞。多年来，科学家们在理解基因包装成开放或封闭结构如何决定基因是开启还是关闭方面取得了进展。这是生物学的基本组成部分。然而，科学家们仍然对这些机制出错时会发生什么知之甚少，不同的细胞类型程序相互竞争。微虫C.秀丽线虫有一个独特的特征，即每个胚胎中的每种细胞类型都是以完全相同的方式形成的。这为解决这一问题提供了一个独特的机会。卡茨实验室将利用这些蠕虫中的不变胚胎来学习当一个错误的程序与正常程序一起被激活时，细胞如何反应的规则。这将解决生物学的一个基本方面，对许多不同和重要的过程有广泛的影响。Katz实验室发现，H3 K4 me 2去甲基化酶LSD 1与H3 K9甲基转移酶MET-2一起沿着起作用，作为表观遗传重编程开关，在受精时用抑制性修饰H3 K9 me 2取代活性组蛋白修饰H3 K4 me 2。在spr-5;met-2突变体中，组蛋白甲基化的不适当遗传导致#8764;200个关键生殖系基因在体细胞中异位表达，从而导致发育延迟。该模型提供了一个独特的机会，以了解不适当的遗传染色质如何影响转录，以及一个发育程序的表达如何影响试图指定不同发育程序的细胞。为了解决这个问题，Katz实验室将利用不变式C。elegans谱系，以确定SPR-5;Met-2突变体中的单细胞分辨如何影响染色质、基因表达和细胞命运。该项目是对Katz实验室追求的更广泛影响的高度补充。在过去5年的NSF资助中，埃默里大学的Katz实验室与附近的文理学院Oglethorpe大学合作，建立了一个管道课程嵌入式本科研究（CURE）课程，生物学专业的学生参加了C。线虫的研究贯穿于整个生物学专业。这在卡茨实验室的一位博士后领导的顶点课程中达到高潮，学生们在一个学期的大部分课堂时间都花在了原创的C上。与卡茨实验室正在进行的实验有关的线虫研究项目。由于管道治愈，大多数生物学专业现在参与真实的研究，初步调查表明，这种真实的研究可以概括的经验，通常只有在一个主要的研究型大学的学徒式的方法。为了继续降低文理学院获得真实研究的门槛，卡茨实验室现在提议为每个生物学专业的学生提供在奥格尔索普大学课堂上进行论文研究的机会。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

项目成果

Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally

• DOI: 10.7554/elife.08848
• 发表时间: 2016-01
• 期刊: eLife
• 影响因子: 7.7
• 作者: Jadiel A. Wasson;A. K. Simon;D. A. Myrick;Gernot Wolf;Shawn P. Driscoll;S. Pfaff;T. Macfarlan;D. Katz

SPR-1/CoREST facilitates the maternal epigenetic reprogramming of the histone demethylase SPR-5/LSD1

SPR-1/CoREST 促进组蛋白去甲基化酶 SPR-5/LSD1 的母体表观遗传重编程

• DOI: 10.1093/genetics/iyad005
• 发表时间: 2023
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Carpenter, Brandon S;Scott, Alyssa;Goldin, Robert;Chavez, Sindy R;Rodriguez, Juan D;Myrick, Dexter A;Curlee, Marcus;Schmeichel, Karen L;Katz, David J
• 通讯作者: Katz, David J

Repressive H3K9me2 protects lifespan against the transgenerational burden of COMPASS activity in C. elegans

• DOI: 10.7554/elife.48498
• 发表时间: 2019-12-09
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Lee, Teresa Wei-sy;David, Heidi Shira;Katz, David John
• 通讯作者: Katz, David John

Lineage Tracing and Single-Cell RNA-seq in C. elegans to Analyze Transgenerational Epigenetic Phenotypes Inherited from Germ Cells.

线虫中的谱系追踪和单细胞 RNA-seq 分析生殖细胞遗传的跨代表观遗传表型。

• DOI: 10.1007/978-1-0716-3259-8_3
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Rodriguez,JuanD;Katz,DavidJ
• 通讯作者: Katz,DavidJ

A Model for Epigenetic Inhibition via Transvection in the Mouse

通过小鼠转染进行表观遗传抑制的模型

• DOI: 10.1534/genetics.117.201913
• 发表时间: 2017
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Rodriguez, Juan D;Myrick, Dexter A;Falciatori, Ilaria;Christopher, Michael A;Lee, Teresa W;Hannon, Gregory J;Katz, David J
• 通讯作者: Katz, David J