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

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

doi:10.7554/elife.65884

Teresa Romeo Luperchio, Leandros Boukas + Show 6 more

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https://doi.org/10.7554/elife.65884

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Abstract

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.

Highlights

Mapping causal disease-associated epigenetic variationA long-standing and fundamental problem in epigenetics is the identification of specific epigenetic changes that causally mediate phenotypes through the alteration of transcriptional states
For 724 of the 733 (98.8%), accessibility is altered in the same direction in the two syndromes (Figure 2B; Figure 2—source data 1). Out of these 724 promoter peaks disrupted in both Kabuki syndrome type 1 (KS1) and Kabuki types 2 (KS2), we discovered that approximately 67 % are differential in Rubinstein-T aybi type 1 (RT1) as well (Figure 2C; p < 2.2e-16, 5 RT1 vs. 7 wild-type mice), again with highly concordant effect sizes (Figure 2D)
We have taken a first step toward validating this hypothesis, by showing that three Mendelian Disorder of the Epigenetic Machinery (MDEM) caused by loss-o f-function variants in three distinct epigenetic regulators have shared alterations at the chromatin and gene expression level in B cells

Summary

Introduction

A long-standing and fundamental problem in epigenetics is the identification of specific epigenetic changes that causally mediate phenotypes through the alteration of transcriptional states. Encoding for epigenetic regulators, which are generally very intolerant to loss-o f-function variation (Boukas et al, 2019) This implies the following causal chain underlying MDEM pathogenesis: a coding variant disrupts an epigenetic regulator, leading to downstream epigenomic abnormalities, which in turn give rise to the phenotype, likely by perturbing the transcriptome (Figure 1A). Our approach is based on a cardinal and far unexploited feature of MDEMs, namely their overlapping phenotypic features, despite the causative genetic variants disrupting distinct genes Such common MDEM features include intellectual disability, growth defects, and immune dysfunction (Fahrner and Bjornsson, 2019). We hypothesize that these shared phenotypes arise because the different primary genetic defects lead to shared downstream epigenomic alterations, which in turn create shared transcriptomic alterations (Figure 1B). In order to facilitate a direct comparison of the three MDEMs, we only used female mice, as Kdm6a is on the X chromosome (KS2 mouse model), and its complete loss (full knockout) is lethal in male mice

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