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

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 chromati...

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Autores principales:	Teresa Romeo Luperchio, Leandros Boukas, Li Zhang, Genay Pilarowski, Jenny Jiang, Allison Kalinousky, Kasper D Hansen, Hans T Bjornsson
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	histone machinery epigenetics computational methods IgA deficiency Mendelian chromatin Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d34ba8239b0a4fcaabab3999748b7e88
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spelling	oai:doaj.org-article:d34ba8239b0a4fcaabab3999748b7e882021-11-15T07:20:11ZLeveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation10.7554/eLife.658842050-084Xe65884https://doaj.org/article/d34ba8239b0a4fcaabab3999748b7e882021-08-01T00:00:00Zhttps://elifesciences.org/articles/65884https://doaj.org/toc/2050-084XAlthough 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.Teresa Romeo LuperchioLeandros BoukasLi ZhangGenay PilarowskiJenny JiangAllison KalinouskyKasper D HansenHans T BjornssoneLife Sciences Publications Ltdarticlehistone machineryepigeneticscomputational methodsIgA deficiencyMendelianchromatinMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	histone machinery epigenetics computational methods IgA deficiency Mendelian chromatin Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	histone machinery epigenetics computational methods IgA deficiency Mendelian chromatin Medicine R Science Q Biology (General) QH301-705.5 Teresa Romeo Luperchio Leandros Boukas Li Zhang Genay Pilarowski Jenny Jiang Allison Kalinousky Kasper D Hansen Hans T Bjornsson Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
description	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.
format	article
author	Teresa Romeo Luperchio Leandros Boukas Li Zhang Genay Pilarowski Jenny Jiang Allison Kalinousky Kasper D Hansen Hans T Bjornsson
author_facet	Teresa Romeo Luperchio Leandros Boukas Li Zhang Genay Pilarowski Jenny Jiang Allison Kalinousky Kasper D Hansen Hans T Bjornsson
author_sort	Teresa Romeo Luperchio
title	Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
title_short	Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
title_full	Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
title_fullStr	Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
title_full_unstemmed	Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
title_sort	leveraging the mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/d34ba8239b0a4fcaabab3999748b7e88
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Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation

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