Histone methylation by the Kleefstra Syndrome protein EHMT1 mediates homeostatic synaptic scaling.

Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra syndrome-associated protein, EHMT1, plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vivo or in vivo. These findings suggest that changes in chromatin state through H3K9me2 governs a repressive program to achieve synaptic scaling.稳态可塑性（Homeostatic plasticity）作为突触可塑性（synaptic plasticity）的一类，可在发育中及成熟的神经元网络内维持整体兴奋与抑制的精细平衡。尽管稳态可塑性的突触机制已得到充分表征，但其相关的转录程序仍鲜有深入解析。本研究发现，与克利夫斯特拉综合征（Kleefstra syndrome）相关的蛋白EHMT1，可通过响应减弱的神经元放电或感觉输入，在突触缩放（synaptic scaling）中发挥关键且细胞自主的调控作用。慢性神经元活动剥夺会提升神经元组蛋白H3赖氨酸9二甲基化（H3K9me2）的水平——该修饰是EHMT1的催化产物，同时也是基因转录抑制的表观遗传标记。对EHMT1或EHMT2进行基因敲低与药理学阻断，均可抑制H3K9me2的上调及突触缩放的增强。此外，在突触缩放增强过程中，无论是在体内还是体外，EHMT1/2介导的H3K9me2在Bdnf基因启动子区域的沉积均先于BDNF（脑源性神经营养因子，Brain-Derived Neurotrophic Factor）的表达抑制。上述研究结果表明，通过H3K9me2介导的染色质状态改变，可调控一套抑制性转录程序，从而实现突触缩放。