Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
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Curated by eLife
Evaluation Summary:
This manuscript finds common molecular features in the blood of three "Mendelian Disorder of the Epigenetic Machinery" (MDEM) mouse models. These shared features (chromatin accessibility and gene expression) may underlie some of the clinical similarities of these disorders. This work will be of interest to researchers, and to some clinicians studying MDEM and epigenetic variation in mammals. Additional analyses are needed to strengthen the conclusions.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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.
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Author Response:
Reviewer #1 (Public Review):
In this report, the authors describe chromatin accessibility and RNA-seq data in B cells from three mouse models of neurodevelopmental disorders (Kabuki syndromes 1 and 2 and Rubinstein-Taybi syndrome type 1) caused by mutations in related epigenetic regulatory genes. They used ATAC-seq to profile chromatin accessibility and a novel bioinformatics approach to overlay the peaks across different mouse models.
The novelty of our approach is not the way we overlay the peaks. It is the way in which, after we have performed differential analyses following standard practices, we detect differential features (genes/loci) shared across the disorders using conditional p-value distributions
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Evaluation Summary:
This manuscript finds common molecular features in the blood of three "Mendelian Disorder of the Epigenetic Machinery" (MDEM) mouse models. These shared features (chromatin accessibility and gene expression) may underlie some of the clinical similarities of these disorders. This work will be of interest to researchers, and to some clinicians studying MDEM and epigenetic variation in mammals. Additional analyses are needed to strengthen the conclusions.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
In this report, the authors describe chromatin accessibility and RNA-seq data in B cells from three mouse models of neurodevelopmental disorders (Kabuki syndromes 1 and 2 and Rubinstein-Taybi syndrome type 1) caused by mutations in related epigenetic regulatory genes. They used ATAC-seq to profile chromatin accessibility and a novel bioinformatics approach to overlay the peaks across different mouse models. They report that the accessibility profiles can distinguish one KO mouse model from another. Matched RNA-seq data demonstrate that many of these ATAC-seq peaks overlap with transcriptional changes, and may be relevant to disorder biology. Overall, the paper is well written, and the conclusions are supported by the data presented.
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Reviewer #2 (Public Review):
Luperchio et al. have explored examples of Mendelian Disorders of the Epigenetic Machinery (MDEM) to look for common systemic functional epigenetic variation in mouse models of Kabuki Syndrome type 1 (KS1) and 2 (KS2), and Rubinstein-Taybi syndrome 1 (RT1). These MDEMs are caused by mutations in the histone lysine methyltransferase KMT2D that targets H3K4 (KS1), histone lysine demethylase KDM6A that targets H3K27me3 (KS2), and the histone acetyltransferase CREBBP (RT1). Due to certain common immunological phenotypes across these disorders, the authors compared isolated B cell (CD19+) via ATAC-seq and RNA-seq from the mutant mice against age- and sex-matched wild-type littermates. They identified 463 loci and 249 genes that show shared disruption in the 3 models examined, with potential functional impact, …
Reviewer #2 (Public Review):
Luperchio et al. have explored examples of Mendelian Disorders of the Epigenetic Machinery (MDEM) to look for common systemic functional epigenetic variation in mouse models of Kabuki Syndrome type 1 (KS1) and 2 (KS2), and Rubinstein-Taybi syndrome 1 (RT1). These MDEMs are caused by mutations in the histone lysine methyltransferase KMT2D that targets H3K4 (KS1), histone lysine demethylase KDM6A that targets H3K27me3 (KS2), and the histone acetyltransferase CREBBP (RT1). Due to certain common immunological phenotypes across these disorders, the authors compared isolated B cell (CD19+) via ATAC-seq and RNA-seq from the mutant mice against age- and sex-matched wild-type littermates. They identified 463 loci and 249 genes that show shared disruption in the 3 models examined, with potential functional impact, including on IgA deficiency in KS1 and RT1.
Strengths
Mouse models have strong advantages for experimental control. Also, the authors have examined isolated cell-types to reduce the impact of cell-type heterogeneity issues. There is clear merit in examining MDEMs, which possess defined monogenic causes for their epigenomic abnormalities, and as such are excellent models to disentangle specific changes in regulatory mechanisms with potential for novel pathogenic understanding.
Weaknesses
Whilst the authors recognise the strong skew in their findings, with almost all of the shared disrupted peaks being unidirectional towards an open chromatin state - that all three specific MDEMs would not predict - they don't give an adequate explanation for these observations. Also, the authors find that many of the loci identified are not known to be direct KMT2D, KDM6A or CREBBP targets. Therefore, the results identified are found to not fit clearly within functional pathways. To account for their indistinct findings, the authors state this is "counterintuitive to the function of the individual causative genes and may either suggest a previously unexpected role for them or an undescribed systemic compensatory response."
The authors grouping approach in their ATAC-seq analysis, where prior to alignment they merged all the individual bam files into genotype-specific meta-samples, will lead to a loss of power and resolution in their findings. They do correctly exclude intervals overlapping the most recent ENCODE blacklisted regions and also overlay their findings with DHS in B cells for further support to reduce the likelihood they are false positives. However, although different from human population studies, some genetic variability does exist even within these mice substrains including C57BL/6J - as highlighted in recent analysis (Mortazavi et al. BioRxiv 10.1101/2020.03.16.993683).
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