Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation.
Leveraging the Mendelian disorders of the epigenetic machinery to systematically map functional epigenetic variation.
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DOI：
10.7554/elife.65884
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发表时间：
2021-08-31
期刊：
影响因子：
7.7
通讯作者：
Bjornsson HT
中科院分区：
文献类型：
--
作者：
Luperchio TR;Boukas L;Zhang L;Pilarowski G;Jiang J;Kalinousky A;Hansen KD;Bjornsson HT
尽管每种孟德尔表观遗传机制障碍（MDEM）都有不同的致病基因，但有共同的疾病表现。我们假设这种表型趋同是共同的表观遗传改变的结果。为了识别这种共有的改变，我们询问了来自三种 MDEM 小鼠模型（Kabuki [KS] 1 型和 2 型以及 Rubinstein-Taybi 1 型 [RT1] 综合征）的 B 细胞的染色质 (ATAC-seq) 和表达 (RNA-seq) 状态。我们开发了一种新的重叠分析方法，发现广泛的重叠主要集中在基因启动子中。我们发现，启动子处染色质可及性的破坏通常会破坏下游基因的表达，并在所有三个 MDEM 中鉴定出 587 个基因座和 264 个基因具有共同的破坏。多个 IgA 相关基因的细微表达改变共同导致 KS1 和 RT1 中的 IgA 缺乏，但在 KS2 中则不然。我们建议 MDEM 的联合研究为系统地绘制哺乳动物功能性表观遗传变异提供了一种原则性方法。
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.