An augmentation in histone dimethylation at lysine nine residues elicits vision impairment following traumatic brain injury
An augmentation in histone dimethylation at lysine nine residues elicits vision impairment following traumatic brain injury
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DOI：
10.1016/j.freeradbiomed.2019.02.015
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发表时间：
2019-04-01
影响因子：
7.4
通讯作者：
Sen, Nilkantha
中科院分区：
文献类型：
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作者：
Gupta, Rajaneesh;Saha, Pampa;Sen, Nilkantha
每年有超过 170 万美国人受到创伤性脑损伤 (TBI) 的影响，其中约 30% 的 TBI 患者存在视力障碍。视网膜中视网膜神经节细胞 (RGC) 的丧失和视神经轴突变性被归因于 TBI 后的视力障碍；然而，其分子机制尚未阐明。在这里，我们发现赖氨酸 9 残基 (H3K9Me2) 的组蛋白二甲基化增加（由组蛋白甲基转移酶 G9a 的催化活性合成）是 TBI 后视神经 RGC 损失和轴突变性的原因。为了阐明其分子机制，我们发现 H3K9Me2 的增加通过直接相互作用损害核因子 E2 相关因子 2 (Nrf2) 的转录活性，从而降低超氧化物歧化酶 (sod) 和过氧化氢酶等抗氧化剂的 mRNA 水平，从而诱导 RGC 和视神经产生氧化应激。氧化应激的诱导与 RGC 和少突胶质细胞前体细胞 (OPC) 的死亡相关。 OPCs 的死亡与髓鞘形成的减少有关，髓鞘结合蛋白 (MBP) 的表达与视神经中神经丝的变性有关。该事件与 TBI 后轴突逆行运输受损和视神经神经纤维层损失有关。施用 G9a 抑制剂 UNC0638 会减弱 RGC 和视神经中 H3K9Me2 的诱导，随后激活 Nrf2 以减少氧化应激。这一事件与 TBI 后视网膜厚度损失的挽救、视神经变性的减弱以及轴突逆行运输的改善同时发生。
Traumatic Brain Injury (TBI) affects more than 1.7 million Americans each year and about 30% of TBI-patients having visual impairments. The loss of retinal ganglion cells (RGC) in the retina and axonal degeneration in the optic nerve have been attributed to vision impairment following TBI; however, the molecular mechanism has not been elucidated. Here we have shown that an increase in histone di-methylation at lysine 9 residue (H3K9Me2), synthesized by the catalytic activity of a histone methyltransferase, G9a is responsible for RGC loss and axonal degeneration in the optic nerve following TBI. To elucidate the molecular mechanism, we found that an increase in H3K9Me2 results in the induction of oxidative stress both in the RGC and optic nerve by decreasing the mRNA level of antioxidants such as Superoxide dismutase (sod) and catalase through impairing the transcriptional activity of Nuclear factor E2-related factor 2 (Nrf2) via direct interaction. The induction of oxidative stress is associated with death in RGC and oligodendrocyte precursor cells (OPCs). The death in OPCs is correlated with a reduction in myelination, and the expression of myelin binding protein (MBP) in association with degeneration of neurofilaments in the optic nerve. This event allied to an impairment of the retrograde transport of axons and loss of nerve fiber layer in the optic nerve following TBI. An administration of G9a inhibitor, UNC0638 attenuates the induction of H3K9Me2 both in RGC and optic nerve and subsequently activates Nrf2 to reduce oxidative stress. This event was concomitant with the rescue in the loss of retinal thickness, attenuation in optic nerve degeneration and improvement in the retrograde transport of axons following TBI.