Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in theGRNgene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through whichGRNis epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of class I HDACs is sufficient to upregulate PGRN in human neurons, and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression. Moreover, we identify regions in theGRNpromoter in which elevated H3K27 acetylation and transcription factor EB (TFEB) occupancy correlate with HDAC-inhibitor-mediated upregulation of PGRN. These findings have implications for epigenetic andcis-regulatory mechanisms controlling humanGRNexpression and may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD.

中文翻译：

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HDAC抑制剂作为progranulin增强剂治疗额颞痴呆的选择性和动力学要求。

额颞痴呆（FTD）起源于额叶，岛状和前颞叶的神经变性。FTD的常染色体显性原因包括GRN基因中的杂合突变，导致前颗粒蛋白（PGRN）蛋白的单倍剂量不足。最近，尽管对GRNis表观遗传调控的机制仍知之甚少，但组蛋白脱乙酰基酶（HDAC）抑制剂已被确定为PGRN表达的增强剂。使用化学基因组学工具包（包括光生遗传探针），我们显示对I类HDAC的抑制足以上调人神经元中的PGRN，并且只有与它们的目标HDAC复合物具有明显快速结合的抑制剂才能增强PGRN的表达。而且，我们在GRN启动子中确定了H3K27乙酰化和转录因子EB（TFEB）占用率升高与HDAC抑制剂介导的PGRN上调相关的区域。这些发现对控制人类GRN表达的表观遗传和顺式调控机制具有启示意义，并可能促进翻译工作，以开发靶向疗法来治疗PGRN不足的FTD。