Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia
| Autor: | Bradford C. Dickerson, Surya A. Reis, Krista M. Hennig, Angela She, Audrey Lang, Wen-Ning Zhao, Joachim Herz, Ralph Mazitschek, Iren Kurtser, Jenny Lai, Stephen J. Haggarty |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Heterozygote Indoles Light Clinical Biochemistry Induced Pluripotent Stem Cells Haploinsufficiency Biology Hydroxamic Acids Biochemistry Histone Deacetylases Article Epigenesis Genetic Histones 03 medical and health sciences Progranulins Downregulation and upregulation Neural Stem Cells Drug Discovery medicine Humans Epigenetics Enhancer Promoter Regions Genetic Molecular Biology Cells Cultured Pharmacology Genetics Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Neurodegeneration Acetylation medicine.disease Up-Regulation Histone Deacetylase Inhibitors 030104 developmental biology Pyrimidines Frontotemporal Dementia Cancer research Molecular Medicine TFEB Intercellular Signaling Peptides and Proteins RNA Interference Histone deacetylase Frontotemporal dementia |
| Zdroj: | Cell chemical biology. 24(7) |
| ISSN: | 2451-9448 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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