Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells, RNA-seq]

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 exhibits 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, since all these cell-types are subject to effects from the same causative gene, that 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 abnormalities in neurons are mostly distinct from those in B or T cells. This is not because the neuronal abnormalities 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 the regions disrupted in B/T cells do exhibit chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we 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 may not be well-suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery. RNA-seq of T cells (CD90.2+) in mouse models of Kabuki Syndrome 1, Kabuki Syndrome 2, as well as wild-type mice目前已发现多种由表观遗传调控因子（epigenetic regulators）编码区变异引发的孟德尔式发育障碍。表观遗传调控因子广泛表达，且此类障碍通常会在多个不同器官系统中表现出表型特征。当前尚存的一个开放性科学问题是：作为发病根源的染色质紊乱，在不同疾病相关细胞类型中是否具有相似性。从原理上讲，该假设具备可行性：所有受该疾病影响的细胞类型均受同一致病基因调控，该基因功能类型一致（如对组蛋白实施甲基化修饰），且会被同一生殖系变异所破坏。本研究聚焦于1型和2型歌舞伎综合征（Kabuki syndrome）的小鼠模型，研究发现神经元中的染色质可及性异常，大多与B细胞或T细胞中的异常存在显著差异。这一现象并非因为神经元的异常仅发生在仅在神经元中具有活性的调控元件上。神经元（而非B细胞或T细胞）会在CpG岛（CpG islands）以及与衰老相关的调控元件处优先出现染色质紊乱。高灵敏度分析结果显示：B/T细胞中发生紊乱的区域，在神经元中确实存在染色质可及性变化，但此类变化极为细微，且其功能意义尚不明确。最后，本研究鉴定出了一组在三种细胞类型中均发生紊乱的调控元件。本研究结果揭示了表观遗传调控因子变异的细胞特异性效应，同时表明血液来源的表观特征标记（episignatures）或许并不适合用于解析表观遗传机制相关孟德尔障碍的神经发育分子机制。本研究涉及的样本包含1型、2型歌舞伎综合征小鼠模型与野生型小鼠的CD90.2阳性T细胞的RNA测序（RNA-seq）数据。