Boukas Leandros, Luperchio Teresa Romeo, Razi Afrooz, Hansen Kasper D, Bjornsson Hans T
Department of Pediatrics, Children's National Hospital.
Department of Genetic Medicine, Johns Hopkins University School of Medicine.
bioRxiv. 2023 Aug 3:2023.08.01.551456. doi: 10.1101/2023.08.01.551456.
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 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" may not be well-suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery.
目前已发现许多由表观遗传调控因子编码变异引起的孟德尔发育障碍。表观遗传调控因子广泛表达，且这些疾病中的每一种通常都表现出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。原则上这是有可能的，因为所有这些细胞类型都受到来自同一个致病基因的影响，该基因具有相同类型的功能（例如使组蛋白甲基化），并被同一个种系变异所破坏。我们聚焦于1型和2型歌舞伎综合征的小鼠模型，发现神经元中的染色质可及性异常与B细胞或T细胞中的大多不同。这并不是因为神经元异常发生在仅在神经元中活跃的调控元件上。神经元而非B细胞或T细胞在CpG岛和与衰老相关的调控元件处表现出优先的染色质破坏。一项敏感性分析表明，在B/T细胞中被破坏的区域在神经元中确实表现出染色质可及性变化，但这些变化非常细微且功能意义不确定。最后，我们能够鉴定出一小部分在所有三种细胞类型中均被破坏的调控元件。我们的研究结果揭示了表观遗传调控因子变异的细胞背景特异性效应，并表明源自血液的“表观特征”可能不太适合用于理解表观遗传机制孟德尔疾病中神经发育的机制基础。
