acy-1215 and Frontotemporal-Dementia

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.

Topics: Acetylation; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cells, Cultured; Epigenesis, Genetic; Frontotemporal Dementia; Haploinsufficiency; Heterozygote; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Indoles; Induced Pluripotent Stem Cells; Intercellular Signaling Peptides and Proteins; Light; Neural Stem Cells; Progranulins; Promoter Regions, Genetic; Pyrimidines; RNA Interference; Up-Regulation