Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
Li Zhang
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
Genay Pilarowski
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
Kasper D Hansen
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Landspitali University Hospital, Reykjavik, Iceland
Although each Mendelian Disorder of the Epigenetic Machinery (MDEM) has a different causative gene, there are shared disease manifestations. We hypothesize that this phenotypic convergence is a consequence of shared epigenetic alterations. To identify such shared alterations, we interrogate chromatin (ATAC-seq) and expression (RNA-seq) states in B cells from three MDEM mouse models (Kabuki [KS] type 1 and 2 and Rubinstein-Taybi type 1 [RT1] syndromes). We develop a new approach for the overlap analysis and find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often disrupts downstream gene expression, and identify 587 loci and 264 genes with shared disruption across all three MDEMs. Subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1, but not in KS2. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.