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: 9911982
• 负责人: Alyssa Michelle Scott
• 金额: $ 4.55万
• 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/9911982
• 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.

项目概要： 自闭症谱系障碍（ASD）的特征是社会交往的缺陷， 沟通、重复的行为模式和有限的兴趣。虽然这些疾病影响1-2%的 尽管世界人口的增长，导致ASD的潜在机制尚未完全了解。只有10- 20%的自闭症有一个已知的遗传原因，但大多数自闭症研究是使用小鼠进行的。 有单基因突变的模型。这表明，在美国， 80-90%的病例。我们实验室最近的数据表明，母亲遗传的低水平的 LSD 1（赖氨酸特异性脱甲基酶1）可能是小鼠自闭症样行为的一个促成因素。LSD1 是一种表观遗传重编程酶，可去除H3 K4 me 1/2（组蛋白H3赖氨酸4单-和双- 甲基化），其通常与活跃转录的基因相关。这些“活跃的痕迹” 转录卵母细胞的基因需要在早期胚胎的重编程过程中被删除， 转录程序被抑制，正常发育得以继续。完全丧失母体LSD 1 在小鼠中，这种酶导致胚胎停滞在1-2细胞阶段，表明这种酶在胚胎发育过程中的重要性。 早期胚胎的重新编程。在罕见的情况下，当只有部分损失的LSD 1的母亲， 存活的后代表现出类似自闭症的行为，如高度焦虑和重复行为。此外，委员会认为， 随着母体年龄的增加，小鼠晚期卵母细胞中LSD 1的量减少。这 与流行病学数据相关，表明ASD的风险每10年显著增加， 父母年龄的增长。我们假设，由于晚期乳腺癌，母体遗传的LSD 1的数量减少， 母亲的年龄增加了患自闭症的风险。为了验证这一假设，我们将生成三个不同的 在体外使其酶功能降低35-85%的亚纯型Lsd 1等位基因。这些亚型等位基因将 让我们模拟部分缺失的母体表型。我们的目标是发现LSD 1中的细微缺陷- 受精时介导的表观遗传重编程可导致长期的行为后果。具体 目的是1）确定是否有丝分裂遗传组蛋白甲基化作为表观遗传转录 记忆，和2）确定母亲亚型LSD 1在神经发育和行为中的作用。成功 这些目标的完成将确定受精时有缺陷的LSD 1重编程可能导致 通过不适当的遗传组蛋白甲基化，一种新的机制， 潜在的自闭症