Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, Pennsylvania 17033.
Penn State Health Eye Center, Hershey, Pennsylvania 17033.
J Neurosci. 2021 Aug 4;41(31):6775-6792. doi: 10.1523/JNEUROSCI.3102-20.2021. Epub 2021 Jun 30.
Epigenetic modifiers are increasingly being investigated as potential therapeutics to modify and overcome disease phenotypes. Diseases of the nervous system present a particular problem as neurons are postmitotic and demonstrate relatively stable gene expression patterns and chromatin organization. We have explored the ability of epigenetic modifiers to prevent degeneration of rod photoreceptors in a mouse model of retinitis pigmentosa (RP), using rd10 mice of both sexes. The histone modification eraser enzymes lysine demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) are known to have dramatic effects on the development of rod photoreceptors. In the RP mouse model, inhibitors of these enzymes blocked rod degeneration, preserved vision, and affected the expression of multiple genes including maintenance of rod-specific transcripts and downregulation of those involved in inflammation, gliosis, and cell death. The neuroprotective activity of LSD1 inhibitors includes two pathways. First, through targeting histone modifications, they increase accessibility of chromatin and upregulate neuroprotective genes, such as from the Wnt pathway. We propose that this process is going in rod photoreceptors. Second, through nonhistone targets, they inhibit transcription of inflammatory genes and inflammation. This process is going in microglia, and lack of inflammation keeps rod photoreceptors alive. Retinal degenerations are a leading cause of vision loss. RP is genetically very heterogeneous, and the multiple pathways leading to cell death are one reason for the slow progress in identifying suitable treatments for patients. Here we demonstrate that inhibition of LSD1and HDAC1 in a mouse model of RP leads to preservation of rod photoreceptors and visual function, retaining of expression of rod-specific genes, and with decreased inflammation, cell death, and Müller cell gliosis. We propose that these epigenetic inhibitors cause more open and accessible chromatin, allowing expression of neuroprotective genes. A second mechanism that allows rod photoreceptor survival is suppression of inflammation by epigenetic inhibitors in microglia. Manipulation of epigenetic modifiers is a new strategy to fight neurodegeneration in RP.
表观遗传修饰剂正被越来越多地作为潜在的治疗方法来修饰和克服疾病表型。神经系统疾病是一个特别的问题，因为神经元是有丝分裂后细胞，表现出相对稳定的基因表达模式和染色质组织。我们已经探索了表观遗传修饰剂在视网膜色素变性 (RP) 的小鼠模型中预防杆状光感受器变性的能力，使用了 rd10 雌雄小鼠。组蛋白修饰酶赖氨酸去甲基酶 1 (LSD1) 和组蛋白去乙酰化酶 1 (HDAC1) 已知对杆状光感受器的发育有显著影响。在 RP 小鼠模型中，这些酶的抑制剂阻止了杆状细胞的变性，保持了视力，并影响了多个基因的表达，包括维持杆状细胞特异性转录本和下调那些参与炎症、胶质增生和细胞死亡的基因。LSD1 抑制剂的神经保护活性包括两条途径。首先，通过靶向组蛋白修饰，它们增加染色质的可及性并上调神经保护基因，如 Wnt 途径的基因。我们提出，这个过程发生在杆状光感受器中。其次，通过非组蛋白靶点，它们抑制炎症基因和炎症的转录。这个过程发生在小胶质细胞中，缺乏炎症可以使杆状光感受器存活。视网膜变性是视力丧失的主要原因。RP 具有非常异质性的遗传基础，导致细胞死亡的多种途径是为患者确定合适治疗方法进展缓慢的原因之一。在这里，我们证明在 RP 的小鼠模型中抑制 LSD1 和 HDAC1 可导致杆状光感受器和视觉功能的保留，保留杆状细胞特异性基因的表达，同时减少炎症、细胞死亡和 Müller 细胞胶质增生。我们提出，这些表观遗传抑制剂导致更开放和可及的染色质，允许神经保护基因的表达。第二种机制是，表观遗传抑制剂在小胶质细胞中抑制炎症，从而允许杆状光感受器存活。操纵表观遗传修饰剂是治疗 RP 中神经退行性变的一种新策略。
