DNA methylation abnormalities in neurons

Date: Thursday, April 4th at 12:30-13:10 in Askja, room N-132

Title: DNA methylation abnormalities in neurons

Speaker: Juan Ouyang, Phd student at Faculty of Medicine, University of Iceland

Abstract: Mutations in genes encoding epigenetic machinery components commonly lead to intellectual disability and growth retardation, and this group is often collectively called the Mendelian disorders of Epigenetic Machinery (MDEM). Recently, our group and others have uncovered a specific DNA methylation (DNAm) signature in one of these disorders (Kabuki syndrome). Other groups have identified multiple individual DNAm signatures in peripheral blood cells from other patients with EM mutations. Here we hypothesize that DNAm patterns in neurons that are shared among many of these factors may help identify which genes are most important for neuronal dysfunction and thus yield clues into the mechanistic basis of intellectual disability, which is a unifying feature of MDEMs. Currently, we find that DNA methylation patterns show abnormalities in multiple individual EM knockouts (KOs). In addition, there are some overlapping differential methylated regions (DMRs) across at least 12 different EM KOs. We have found that a subset of these DMRs appear to be functionally relevant as they are associated with gene expression changes in both Kmt2a KOs and Dnmt1 KOs. As an example, differentially upregulated genes after comparing Kmt2a-KOs and controls appear enriched for genes involved in neuron development and mitochondrial organization. Moreover, differentiated Kmt2a mutant NPCs express more neuronal maturation markers in contrast to controls and increase the number of DMRs compared with the undifferentiated state, indicating EM genes may play an important role in the establishment of an epigenetic barrier during neuron development by targeting functionally relevant DMRs.