Spinal muscular atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped, cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide (ASO) that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with a nusinersen-like ASO to promote E7 inclusion. Surprisingly, the ASO promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to RNA polymerase II elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the chromatin effects of the ASO, resulting in higher E7 inclusion without large pleiotropic effects. Combined administration of the nusinersen-like ASO and VPA in SMA mice strongly synergizes SMN expression, growth, survival, and neuromuscular function.

脊髓性肌萎缩症 (SMA) 是由SMN1基因突变引起的运动神经元疾病。人类旁系同源基因SMN2的外显子 7 (E7) 主要被跳过，无法弥补SMN1的缺失。Nusinersen 是一种反义寡核苷酸 (ASO)，它通过将剪接抑制因子 hnRNPA1/A2 从内含子 7 中的靶位点置换来上调 E7 包含物和 SMN 蛋白水平。我们表明，通过促进转录延伸，组蛋白脱乙酰酶抑制剂 VPA 与 nusinersen-像 ASO 一样促进 E7 包容。令人惊讶的是，ASO 促进了沉默组蛋白标记 H3K9me2 在SMN2上的部署基因，为抑制 E7 包含的 RNA 聚合酶 II 延伸设置障碍。通过移除障碍，VPA 抵消了 ASO 的染色质效应，从而导致更高的 E7 包含而没有大的多效性效应。在 SMA 小鼠中联合施用 nusinersen 样 ASO 和 VPA 可强烈协同 SMN 表达、生长、存活和神经肌肉功能。