Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.

中文翻译：

---

赖氨酸乙酰转移酶8与大脑发育和综合征性智力障碍有关

表观遗传完整性对于许多真核细胞过程至关重要。一个重要的问题是不同的表观遗传调控因子如何控制发育并影响疾病。赖氨酸乙酰基转移酶8（KAT8）对于组氨酸H4在赖氨酸16（H4K16）处的乙酰化至关重要，赖氨酸16（H4K16）是进化上保守的表观遗传标记。尚不清楚KAT8在脑发育和人类疾病中起什么作用。在这里，我们报告大脑特定的基因敲除小鼠在新皮层和海马显示脑发育不全，以及不正确的神经干细胞和祖细胞（NSPC）的发展。突变的脑皮质神经上皮细胞显示出增殖不良，异常的神经发生，大量的细胞凋亡和少量的H4K16丙酰化。突变的NSPCs形成不良的神经球，而药理性KAT8抑制作用消除了神经球的形成。此外，9名智力残疾，癫痫，自闭症，畸形和其他异常患者中的KAT8变异。这些变体改变了KAT8的染色体桶和催化结构域，从而损害了核小体H4K16乙酰化。丙戊酸盐对至少2个个体有效治疗癫痫。这项研究揭示了KAT8在大脑和NSPC发育中的关键作用，确定了9个具有KAT8变异的个体，并将缺乏的H4K16酰化作用直接与智力障碍，癫痫和其他发育异常联系起来。