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

eLife

Allison Kalinousky¹  Genay Pilarowski¹  Li Zhang¹  Jenny Jiang¹  Teresa Romeo Luperchio¹  Kasper D Hansen²  Leandros Boukas²  Hans T Bjornsson³ 

[1] 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;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;

关键词: histone machinery;    epigenetics;    computational methods;    IgA deficiency;    Mendelian;    chromatin;    Mouse;   

DOI  :  10.7554/eLife.65884

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY