The maternal role of hypomorphic LSD1 and its epigenetic contributions to neurodevelopment

亚形 LSD1 的母体作用及其对神经发育的表观遗传贡献

• 批准号: 9761141
• 负责人: Alyssa Michelle Scott
• 金额: $ 4.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-25 至 2022-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761141
• 关键词: Adult; Affect; Alleles; Anxiety; Behavior; Behavioral; Biological Assay; CRISPR/Cas technology; Caenorhabditis elegans; Caring; Cells; ChIP-seq; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Defect; Deposition; Development; Disease; Economic Burden; Embryo; Enzymes; Epigenetic Process; Exhibits; Failure; Family; Fertilization; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Golgi Apparatus; Heritability; Histone H3; Histones; Human; In Vitro; Individual; Inherited; Intellectual functioning disability; KDM1A gene; Knowledge; Lead; Link; Lysine; Mammals; Maternal Age; Mediating; Memory; Methylation; Mitotic; Modeling; Mus; Mutation; Neuroanatomy; Oocytes; Oogenesis; Outcome; Parental Ages; Patients; Pattern; Phenotype; Population; Proteins; Research; Risk; Role; Series; Services; Social Interaction; Testing; Therapeutic Intervention; Time; Translating; Vertebral column; Work; advanced maternal age; autism spectrum disorder; autistic; autistic behaviour; blastocyst; cost; density; epidemiologic data; histone methylation; human model; interest; mouse model; mutant; neurodevelopment; novel; offspring; programs; repetitive behavior; social; social communication; transcriptome sequencing

PROJECT SUMMARY: Autism spectrum disorders (ASDs) are characterized by defects in social interactions and communication, repetitive behavior patterns, and restricted interests. Although these disorders affect 1-2% of the world’s population, the underlying mechanisms that contribute to ASDs are not fully understood. Only 10- 20% of ASDs have a known genetic cause, and yet the majority of autism research is performed using mouse models that have a monogenic mutation. This presents a gap in knowledge about the causes of ASDs in the other 80-90% of cases. Recent data from our lab suggests that maternal inheritance of reduced levels of the enzyme LSD1 (lysine specific demethylase 1), may be a contributing factor to autistic-like behavior in mice. LSD1 is an epigenetic reprogramming enzyme that removes H3K4me1/2 (histone H3 lysine 4 mono- and di- methylation), which are typically associated with actively transcribed genes. These ‘active marks’ around transcribing oocyte genes need to be erased during reprogramming in the early embryo in order for the oogenesis transcriptional program to be repressed and normal development to continue. A complete loss of maternal LSD1 in mice results in embryonic arrest at the 1-2 cell stage, indicating the importance of this enzyme during reprogramming of the early embryo. On rare occasions when there is only partial loss of LSD1 maternally, the surviving offspring exhibit autistic-like behaviors such as high anxiety and repetitive behaviors. Furthermore, there is a decrease in the amount of LSD1 in late stage oocytes in mice with increasing maternal age. This correlates with epidemiological data showing that the risk of ASDs increase significantly with each 10-year increase in parental age. We hypothesize that reduced amounts of maternally-inherited LSD1 due to advanced maternal age contributes to the risk of developing ASDs. To test this hypothesis, we’re generating three different hypomorphic Lsd1 alleles that decrease its enzymatic function 35-85% in vitro. These hypomorphic alleles will allow us to mimic the partial loss maternal phenotype. Our goal is to discover how subtle defects in LSD1- mediated epigenetic reprogramming at fertilization can result in long-term behavioral consequences. The specific aims are to 1) determine whether mitotically heritable histone methylation serves as an epigenetic transcriptional memory, and 2) identify the role of maternal hypomorphic LSD1 in neurodevelopment and behavior. Successful completion of these aims will establish that defective LSD1 reprogramming at fertilization can lead to the development of autistic-like behaviors via inappropriately inherited histone methylation, a novel mechanism potentially underlying ASDs.

项目摘要： 自闭症谱系障碍（ASD）的特征是社交互动中的缺陷和 沟通，重复行为模式和限制利益。尽管这些疾病影响了1-2％ 世界人口，有助于ASD的基本机制尚不完全了解。只有10- 20％的ASD具有已知遗传原因，但大多数自闭症研究是使用小鼠进行的 具有单基因突变的模型。这列出了有关ASD的原因的知识差距 其他80-90％的案件。我们实验室的最新数据表明，降低水平的物质继承 酶LSD1（赖氨酸特异性去甲基酶1），可能是小鼠加速行为的一个因素。 LSD1 是一种去除H3K4ME1/2的表观遗传重编程酶（组蛋白H3赖氨酸4单和DI- 甲基化），通常与主动转录基因有关。这些“主动标记”周围 在早期胚胎中重新编程时，需要擦除转录卵母细胞基因，以使卵子发生 转录程序要复制，并需要正常发展。孕产妇LSD1的完全损失 在小鼠中导致1-2个细胞阶段的胚胎停滞，表明该酶在期间的重要性 重新编程早期胚胎。在极少数情况下，只有部分损失LSD1， 幸存的后代裸露的加速行为，例如高焦虑和重复行为。此外， 随着孕妇年龄升高的小鼠，晚期卵母细胞的LSD1量减少。这 与流行病学数据相关，表明每10年的ASD风险显着增加 父母年龄的增加。我们假设由于先进而导致的主要生存的LSD1减少了 产妇年龄有助于发展ASD的风险。为了检验这一假设，我们生成了三种不同的 降低其酶促功能35-85％体外的LSD1等位基因。这些型肌科等位基因将 允许我们模仿部分损失的遗产表型。我们的目标是发现LSD1-的细微缺陷如何 受精时介导的表观遗传重编程会导致长期行为后果。具体 目的是1）确定有丝分裂性可遗传的组蛋白甲基化是否用作表观遗传转录 记忆和2）确定母体肌型LSD1在神经发育和行为中的作用。成功的 这些目标的完成将确定有缺陷的LSD1在受精时重编程会导致 通过不当遗传的组蛋白甲基化发展加速行为，这是一种新型机制 潜在的基础ASD。