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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：自闭症谱系障碍 (ASD) 的特点是社交互动缺陷和沟通、重复行为模式和兴趣受限，尽管这些障碍影响了 1-2% 的人。就世界人口而言，导致自闭症谱系障碍的根本机制尚不完全清楚。只有 10-。 20% 的自闭症谱系障碍有已知的遗传原因，但大多数自闭症研究都是使用小鼠进行的具有单基因突变的模型这表明人们对自闭症谱系障碍 (ASD) 原因的了解存在空白。其他 80-90% 的病例来自我们实验室的最新数据表明母系遗传水平降低。 LSD1 酶（赖氨酸特异性去甲基酶 1）可能是导致小鼠自闭症样行为的一个因素。是一种表观遗传重编程酶，可去除 H3K4me1/2（组蛋白 H3 赖氨酸 4 单和双）甲基化），通常与这些活跃转录的基因相关。为了卵子发生，在早期胚胎重编程过程中需要删除转录卵母细胞基因转录程序受到抑制，母体 LSD1 完全丧失，正常发育得以继续。在小鼠中导致胚胎停滞在 1-2 细胞阶段，表明该酶在胚胎发育过程中的重要性早期胚胎的重新编程在极少数情况下，当母体仅部分丢失 LSD1 时，幸存的后代表现出类似自闭症的行为，例如高度焦虑和重复行为。随着母体年龄的增加，小鼠晚期卵母细胞中 LSD1 的数量减少。与流行病学数据相关，显示 ASD 风险每 10 年显着增加由于父母年龄的增加，我们努力减少母系遗传的 LSD1 的数量。母亲年龄会增加患自闭症谱系障碍的风险为了检验这一假设，我们提出了三种不同的方法。低等位 Lsd1 等位基因会在体外降低其酶功能 35-85%。让我们能够模仿部分缺失的母体表型我们的目标是发现 LSD1- 中的微妙缺陷。受精时介导的表观遗传重编程可能会导致长期的行为后果。目的是 1) 确定有丝分裂可遗传的组蛋白甲基化是否作为表观遗传转录记忆，2) 确定母体低形态 LSD1 在神经发育和行为成功中的作用。这些目标的完成将证明受精时 LSD1 重编程缺陷可能导致通过不适当遗传的组蛋白甲基化（一种新机制）发展出类似自闭症的行为潜在的 ASD。