Yamada Ayumi, Hirasawa Takae, Nishimura Kayako, Shimura Chikako, Kogo Naomi, Fukuda Kei, Kato Madoka, Yokomori Masaki, Hayashi Tetsutaro, Umeda Mana, Yoshimura Mika, Iwakura Yoichiro, Nikaido Itoshi, Itohara Shigeyoshi, Shinkai Yoichi
Cellular Memory Laboratory, Cluster for Pioneering Research, RIKEN, Wako, Saitama, Japan.
Department of Biosciences, School of Science and Engineering, Teikyo University, 1-1 Toyosatodai, Utsunomiya, Tochigi, Japan.
iScience. 2021 Jun 17;24(7):102741. doi: 10.1016/j.isci.2021.102741. eCollection 2021 Jul 23.
Haploinsufficiency of , which encodes histone H3 lysine 9 (H3K9) methyltransferase G9a-like protein (GLP), causes Kleefstra syndrome (KS), a complex disorder of developmental delay and intellectual disability. Here, we examined whether postnatal supply of GLP can reverse the neurological phenotypes seen in mice as a KS model. Ubiquitous GLP supply from the juvenile stage ameliorated behavioral abnormalities in mice. Postnatal neuron-specific GLP supply was not sufficient for the improvement of abnormal behaviors but still reversed the reduction of H3K9me2 and spine number in mice. Interestingly, some inflammatory genes, including , were upregulated and activated microglial cells increased in the brain, and such phenotypes were also reversed by neuron-specific postnatal GLP supply. inactivation canceled the microglial and spine number phenotypes in the mice. Thus, H3K9me2 and some neurological phenotypes are reversible, but behavioral abnormalities are more difficult to improve depending on the timing of GLP supply.
编码组蛋白H3赖氨酸9（H3K9）甲基转移酶G9a样蛋白（GLP）的基因单倍剂量不足会导致克莱夫斯特拉综合征（KS），这是一种伴有发育迟缓与智力残疾的复杂病症。在此，我们研究了产后补充GLP是否能够逆转作为KS模型的该基因敲除小鼠所出现的神经学表型。从幼年阶段开始全身性补充GLP可改善该基因敲除小鼠的行为异常。产后神经元特异性补充GLP不足以改善异常行为，但仍可逆转该基因敲除小鼠中H3K9me2的减少以及脊柱数量的减少。有趣的是，包括某些基因在内的一些炎症基因上调，且该基因敲除小鼠大脑中活化的小胶质细胞增多，而产后神经元特异性补充GLP也可逆转这些表型。该基因失活消除了该基因敲除小鼠中的小胶质细胞和脊柱数量表型。因此，H3K9me2和一些神经学表型是可逆的，但行为异常根据GLP补充的时机不同更难改善。
