Department of Pediatrics, Children's National Hospital, Washington, DC 20010, USA.
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Genome Res. 2024 Jun 25;34(5):696-710. doi: 10.1101/gr.278416.123.
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.
现在已经发现了许多由表观遗传调节剂编码变异引起的孟德尔发育障碍。表观遗传调节剂广泛表达，这些疾病中的每一种通常都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，染色质的破坏——发病机制的根源——在不同的与疾病相关的细胞类型中是否相似。从理论上讲，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所破坏。我们专注于 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变化与 B 或 T 细胞中的变化大多不同。这并不是因为神经元中的染色质可及性变化发生在仅在神经元中活跃的调节元件上。神经元而非 B 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 细胞中破坏的调节元件确实在神经元中显示出染色质可及性变化，但这些变化非常细微，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节元件。我们的研究结果揭示了表观遗传调节剂变异在细胞环境特异性中的作用，并表明虽然血液衍生的 epi 特征在诊断上很有用，但可能不适合理解表观遗传机制中孟德尔发育障碍的机制基础。
