Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1^+/− adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2^+/− mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1^+/− mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1^+/− mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.

中文翻译：

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H3K9甲基化增加和原钙粘蛋白表达受损与Kleefstra综合征的认知功能障碍有关

EHMT1的单倍剂量不足会导致人患有Kleefstra综合征，这是一种具有智力残疾，自闭症谱系障碍和其他发育缺陷的疾病。尽管已证明EHMT1及其旁系同源物EHMT2是负责二甲基化H3K9（H3K9me2）沉积的组蛋白甲基转移酶，但Kleefstra综合征中表观遗传功能障碍的确切性质仍然未知。在这里，我们发现Ehmt1 ^+/-成年小鼠大脑的表观基因组显示出H3K9me2 / 3的显着增加，这与原钙粘蛋白（神经元多样性的主要调节剂）的表达受损有关。出生时已经存在H3K9me3的增加，表明在胚胎发生过程中建立了异常的甲基化模式。有趣的是，我们发现Ehmt2 ^+/-小鼠既没有出现H3K9me2 / 3的显着增加，也没有在Ehmt1 ^+/-小鼠中发现的认知缺陷，这表明功能的进化多样化。我们在Ehmt1 ^+/-小鼠中增加H3K9me3的发现是第一个支持以下观点的观点：EHMT1可以淬灭其他组蛋白甲基转移酶的三甲基化沉积，最终导致神经认知功能受损。我们对Kleefstra综合征的表观遗传病理生理学的见识可能为该病治疗策略的未来发展提供指导。