Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically shows phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption—the root of the pathogenesis—is similar in the different disease-relevant cell types. This is possible in principle, because all these cell types are subject to effects from the same causative gene, which has the same kind of function (e.g., methylates histones) and is disrupted by the same germline variant. We focus on mouse models for Kabuki syndrome types 1 and 2 and find that the chromatin accessibility changes in neurons are mostly distinct from changes in B or T cells. This is not because the neuronal accessibility changes occur at regulatory elements that are only active in neurons. Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging. A sensitive analysis reveals that regulatory elements disrupted in B/T cells do show chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we are able to identify a small set of regulatory elements disrupted in all three cell types. Our findings reveal the cellular-context-specific effect of variants in epigenetic regulators and suggest that blood-derived episignatures, although useful diagnostically, may not be well suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery.

中文翻译：

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歌舞伎综合征小鼠 CpG 岛和衰老相关区域的神经元特异性染色质破坏


现在已经发现了许多由表观遗传调节因子的编码变异引起的孟德尔发育障碍。表观遗传调节因子广泛表达，每种疾病通常表现出来自许多不同器官系统的表型表现。一个悬而未决的问题是，染色质破坏（发病机制的根源）在不同的疾病相关细胞类型中是否相似。原则上这是可能的，因为所有这些细胞类型都受到相同致病基因的影响，该基因具有相同的功能（例如甲基化组蛋白）并被相同的种系变异破坏。我们关注歌舞伎综合症 1 型和 2 型的小鼠模型，发现神经元中染色质可及性的变化与 B 或 T 细胞的变化大体不同。这并不是因为神经元可达性的变化发生在仅在神经元中活跃的调节元件处。神经元（而非 B 细胞或 T 细胞）在 CpG 岛和与衰老相关的调节元件处表现出优先的染色质破坏。敏感分析表明，B/T 细胞中被破坏的调节元件确实表现出神经元中染色质可及性的变化，但这些变化非常微妙且具有不确定的功能意义。最后，我们能够识别所有三种细胞类型中被破坏的一小组调控元件。我们的研究结果揭示了表观遗传调节因子变异的细胞环境特异性效应，并表明血液来源的表观特征虽然在诊断上有用，但可能不太适合理解表观遗传机制孟德尔紊乱中神经发育的机制基础。