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

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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.