Huntington’s disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. Altered histone modifications and epigenetic mechanisms are closely associated with HD suggesting that transcriptional repression may play a pathogenic role. Epigenetic compounds have significant therapeutic effects in cellular and animal models of HD, but they have not been successful in clinical trials. Herein, we report that dSETDB1/ESET, a histone methyltransferase (HMT), is a mediator of mutant HTT-induced degeneration in a fly HD model. We found that nogalamycin, an anthracycline antibiotic and a chromatin remodeling drug, reduces trimethylated histone H3K9 (H3K9me3) levels and pericentromeric heterochromatin condensation by reducing the expression of Setdb1/Eset. H3K9me3-specific ChIP-on-ChIP analysis identified that the H3K9me3-enriched epigenome signatures of multiple neuronal pathways including Egr1, Fos, Ezh1, and Arc are deregulated in HD transgenic (R6/2) mice. Nogalamycin modulated the expression of the H3K9me3-landscaped epigenome in medium spiny neurons and reduced mutant HTT nuclear inclusion formation. Moreover, nogalamycin slowed neuropathological progression, preserved motor function, and extended the life span of R6/2 mice. Together, our results indicate that modulation of SETDB1/ESET and H3K9me3-dependent heterochromatin plasticity is responsible for the neuroprotective effects of nogalamycin in HD and that small compounds targeting dysfunctional histone modification and epigenetic modification by SETDB1/ESET may be a rational therapeutic strategy in HD.

亨廷顿舞蹈病（HD）是一种常染色体显性遗传神经病，由亨廷顿（HTT）基因第1外显子的CAG重复序列扩增引起。组蛋白修饰和表观遗传机制的改变与高清密切相关，提示转录抑制可能起着致病作用。表观遗传化合物在HD细胞和动物模型中具有显着的治疗作用，但在临床试验中并未取得成功。在这里，我们报告说，dSETDB1 / ESET，一种组蛋白甲基转移酶（HMT），是突变体HTT的介体。HD模型中引起的变性。我们发现，诺加霉素，蒽环类抗生素和染色质重塑药物，通过减少Setdb1 / Eset的表达，降低了三甲基化组蛋白H3K9（H3K9me3）的水平，并降低了着丝粒异染色质的缩合。H3K9me3特定的ChIP-on-ChIP分析确定了H3K9me3丰富的表观基因组签名的多个神经元途径，包括Egr1，Fos，Ezh1和Arc在HD转基因（R6 / 2）小鼠中被释放。诺加霉素调节中棘状神经元中H3K9me3修饰的表观基因组的表达，并减少突变型HTT核包涵体的形成。此外，诺加霉素减缓了神经病理学进程，保留了运动功能，并延长了R6 / 2小鼠的寿命。总之，我们的结果表明，SETDB1 / ESET和依赖H3K9me3的异染色质可塑性的调节是诺加霉素在HD中的神经保护作用的原因，而针对靶向功能障碍的组蛋白修饰和SETDB1 / ESET的表观遗传修饰的小化合物可能是HD的合理治疗策略。