Patterns of histone methylation can be propagated through cell division as a form of transcriptional memory to maintain transcriptional states. At fertilization, this histone methylation must be reprogrammed to prevent the inappropriate inheritance of transcriptional states in the progeny. My lab has shown in both C. elegans and mice, that lack of reprogramming histone methylation at fertilization can lead to the epigenetic inheritance of abnormal phenotypes. These phenotypes are reminiscent of defects observed in patients with mutations in the H3K4me1/2 demethylase LSD1/KDM1A, and in Kabuki Syndrome, caused by mutations in other histone modifying enzymes. This raises the possibility that maternal germ line reprogramming may be a susceptibility point through which human mutations in histone modifying enzymes contribute to human disease. To investigate this possibility my lab has generated a new hypomorphic allele of LSD1 in mouse oocytes. In this proposal, we will use this new LSD1 mouse to address the following questions. Can hypomorphic maternal LSD1 at fertilization lead to developmental delay and learning deficits observed in human LSD1 patients and Kabuki Syndrome patients? How does maternal age and genetic background modulate phenotypes caused by hypomorphic maternal LSD1? Does LSD1 cooperate in maternal reprogramming with the H3K9 methyltransferase SETDB1? What is the mechanism through which maternal loss of LSD1 contributes to inherited defects? What are the genes/pathways that are affected by maternal loss of LSD1? How does hypomorphic LSD1 at fertilization affect imprinted gene expression? Addressing these questions will begin to determine whether defects in maternal epigenetic reprogramming can contribute to inherited human disease.