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  • Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra syndrome.

Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra syndrome.

iScience (2021-07-15)
Ayumi Yamada, Takae Hirasawa, Kayako Nishimura, Chikako Shimura, Naomi Kogo, Kei Fukuda, Madoka Kato, Masaki Yokomori, Tetsutaro Hayashi, Mana Umeda, Mika Yoshimura, Yoichiro Iwakura, Itoshi Nikaido, Shigeyoshi Itohara, Yoichi Shinkai
ABSTRACT

Haploinsufficiency of EHMT1, 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 Ehmt1 Δ/+ mice as a KS model. Ubiquitous GLP supply from the juvenile stage ameliorated behavioral abnormalities in Ehmt1 Δ/+ 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 Ehmt1 Δ/+ mice. Interestingly, some inflammatory genes, including IL-1β (Il1b), were upregulated and activated microglial cells increased in the Ehmt1 Δ/+ brain, and such phenotypes were also reversed by neuron-specific postnatal GLP supply. Il1b inactivation canceled the microglial and spine number phenotypes in the Ehmt1 Δ/+ mice. Thus, H3K9me2 and some neurological phenotypes are reversible, but behavioral abnormalities are more difficult to improve depending on the timing of GLP supply.

MATERIALS
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Product Description

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