Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

Angela She, Iren Kurtser, Surya A. Reis, Krista Hennig, Jenny Lai, Audrey Lang, Wen Ning Zhao, Ralph Mazitschek, Bradford C. Dickerson, Joachim Herz, Stephen J. Haggarty

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)892-906.e5
JournalCell Chemical Biology
Volume24
Issue number7
DOIs
StatePublished - Jul 20 2017

Keywords

  • HDAC inhibitor
  • chemogenomics
  • epigenetic regulation
  • frontotemporal dementia
  • frontotemporal lobar degeneration
  • human neuronal culture
  • optoepigenetic
  • stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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  • Cite this

    She, A., Kurtser, I., Reis, S. A., Hennig, K., Lai, J., Lang, A., Zhao, W. N., Mazitschek, R., Dickerson, B. C., Herz, J., & Haggarty, S. J. (2017). Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia. Cell Chemical Biology, 24(7), 892-906.e5. https://doi.org/10.1016/j.chembiol.2017.06.010