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

Cell Chem Biol. 2017 Jul 20;24(7):892-906.e5. doi: 10.1016/j.chembiol.2017.06.010. Epub 2017 Jul 14.

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.

Keywords: HDAC inhibitor; chemogenomics; epigenetic regulation; frontotemporal dementia; frontotemporal lobar degeneration; human neuronal culture; optoepigenetic; stem cells.

MeSH terms

  • Acetylation / drug effects
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cells, Cultured
  • Epigenesis, Genetic
  • Frontotemporal Dementia / drug therapy
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology
  • Haploinsufficiency / genetics
  • Heterozygote
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Hydroxamic Acids / therapeutic use
  • Indoles / chemistry
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Induced Pluripotent Stem Cells / cytology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Light
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Progranulins
  • Promoter Regions, Genetic
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • RNA Interference
  • Up-Regulation / drug effects
  • Up-Regulation / radiation effects

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Indoles
  • Intercellular Signaling Peptides and Proteins
  • PCI 34051
  • Progranulins
  • Pyrimidines
  • tubastatin A
  • Histone Deacetylases
  • ricolinostat