Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Departamento de Fisiología, Biología Molecular y Celular and CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), 1428 Buenos Aires, Argentina.
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Cell. 2022 Jun 9;185(12):2057-2070.e15. doi: 10.1016/j.cell.2022.04.031.
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）是一种由 SMN1 基因突变引起的运动神经元疾病。人类同源基因 SMN2 的外显子 7（E7）主要被跳过，无法弥补 SMN1 的缺失。诺西那生钠是一种反义寡核苷酸（ASO），通过将 hnRNPA1/A2 剪接抑制剂从其 7 号内含子的靶位上置换出来，从而上调 E7 包含和 SMN 蛋白水平。我们表明，通过促进转录延伸，组蛋白去乙酰化酶抑制剂 VPA 与类似诺西那生钠的 ASO 合作，促进 E7 包含。令人惊讶的是，该 ASO 促进了沉默组蛋白标记 H3K9me2 在 SMN2 基因上的部署，在 RNA 聚合酶 II 延伸过程中形成一个阻碍，从而抑制 E7 包含。通过去除阻碍物，VPA 抵消了 ASO 的染色质效应，导致 E7 包含增加而没有大的多效性影响。在 SMA 小鼠中联合使用类似诺西那生钠的 ASO 和 VPA 可强烈协同增强 SMN 表达、生长、存活和神经肌肉功能。
