Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia.
Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia.
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DOI：
10.1016/j.chembiol.2017.06.010
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发表时间：
2017-07-20
影响因子：
8.6
通讯作者：
Haggarty SJ
中科院分区：
文献类型：
--
作者：
She A;Kurtser I;Reis SA;Hennig K;Lai J;Lang A;Zhao WN;Mazitschek R;Dickerson BC;Herz J;Haggarty SJ
额颞叶痴呆（FTD）是由额叶、岛叶和前颞叶的神经变性引起的。FTD的常染色体显性病因包括GRN基因杂合突变，导致颗粒蛋白原（PGRN）蛋白单倍不足。最近，组蛋白去乙酰化酶（HDAC）抑制剂已被确定为PGRN表达的增强剂，但GRN的表观遗传调控机制仍然知之甚少。使用化学基因组学工具包，包括光表观遗传探针，我们表明I类HDAC的抑制足以上调人神经元中的PGRN，并且仅具有明显快速结合其靶HDAC复合物的抑制剂能够增强PGRN表达。此外，我们确定了GRN启动子中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GRN表达的表观遗传和顺式调节机制具有影响，并可能促进翻译工作，以开发治疗PGN缺陷型FTD的靶向治疗剂。She等人显示I类HDAC的抑制足以上调人神经元中的颗粒蛋白前体（PGRN），并且仅快速结合HDAC抑制剂能够增强PGRN表达。这些发现可能会推动翻译工作，以开发治疗PGRN缺陷疾病的靶向治疗药物。
Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is 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 the GRN promoter 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 and cis-regulatory mechanisms controlling human GRN expression and may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD. She et al. show that inhibition of Class I HDACs is sufficient to upregulate progranulin (PGRN) in human neurons and only fast-binding HDAC inhibitors are capable of enhancing PGRN expression. These findings may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient diseases.
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影响因子：
4.2
作者：
Fass, Daniel M.;Shah, Rishita;Ghosh, Balaram;Hennig, Krista;Norton, Stephanie;Zhao, Wen-Ning;Reis, Surya A.;Klein, Peter S.;Mazitschek, Ralph;Maglathlin, Rebecca L.;Lewis, Timothy A.;Haggarty, Stephen J.
通讯作者：
Haggarty, Stephen J.
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
5.6
作者：
Alquezar, Carolina;Esteras, Noemi;Martin-Requero, Angeles
通讯作者：
Martin-Requero, Angeles
影响因子：
46.9
作者：
Bantscheff, Marcus;Hopf, Carsten;Drewes, Gerard
通讯作者：
Drewes, Gerard
影响因子：
4.8
作者：
Chou, C. James;Herman, David;Gottesfeld, Joel M.
通讯作者：
Gottesfeld, Joel M.