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

项目总结： 自闭症谱系障碍(ASD)的特征是社交缺陷和 交流、重复的行为模式和受限的利益。尽管这些疾病影响到1-2%的 对于世界人口来说，导致自闭症的潜在机制还没有完全了解。只有10- 20%的自闭症有已知的遗传原因，但大多数自闭症研究都是在小鼠身上进行的 有单基因突变的模型。这造成了人们对自闭症病因的认识上的差距 其他80%-90%的病例。我们实验室的最新数据表明，母体遗传水平降低 酶LSD1(赖氨酸特异性脱甲基酶1)可能是导致小鼠孤独症样行为的一个因素。LSD1 是一种表观遗传重编程酶，它能去除H3K4me1/2(组蛋白H3赖氨酸4单链和双链- 甲基化)，这通常与活跃转录的基因有关。这些“活跃的印记” 在早期胚胎中，转录的卵母细胞基因需要在重编程过程中被擦除，以便进行卵子发生 转录程序被抑制，正常发育继续进行。母体LSD1的完全丧失 在小鼠中导致胚胎停滞在1-2细胞阶段，表明这种酶在 对早期胚胎进行重新编程。在极少数情况下，仅有部分LSD1母体丢失， 存活下来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， 随着孕龄的增加，小鼠晚期卵母细胞中LSD1的数量减少。这 与流行病学数据相关，表明患自闭症的风险每10年显著增加 父母年龄的增加。我们假设，母亲遗传的LSD1的数量减少是由于晚期 产妇年龄增加了患自闭症的风险。为了检验这一假设，我们生成了三种不同的 在体外使其酶功能降低35-85%的亚型LSD1等位基因。这些亚形等位基因将 允许我们模仿部分丢失的母体表型。我们的目标是发现LSD1中的细微缺陷- 受精时介导性的表观遗传重编程可能导致长期的行为后果。具体的 目的是1)确定有丝分裂可遗传组蛋白甲基化是否作为表观遗传转录 以及2)确定母体低形态LSD1在神经发育和行为中的作用。成功 这些目标的完成将确定在受精时有缺陷的LSD1重新编程可能导致 通过不适当遗传的组蛋白甲基化发展自闭症样行为，这是一种新的机制 潜在的自闭症。

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.