Journal Article

Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation

Luperchio, Teresa Romeo, Pilarowski, Genay, Jiang, Jenny, Zhang, Li, Bjornsson, Hans T, Hansen, Kasper D, Boukas, Leandros, Kalinousky, Allison

2021

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Analysis / Animal models / B cells / Chromatin / Computational and Systems Biology / computational methods / Disease / Epigenetic inheritance / Epigenetics / Experiments / Gene expression / Genetic research / Genetics / Genetics and Genomics / Genomes / Genotype & phenotype / Handicapped accessibility / histone machinery / IgA deficiency / Immunoglobulin A / Intellectual disabilities / Lymphocytes B / Mendelian / Pathogenesis / Promoters