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2017 ; 24
(7
): 892-906.e5
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English Wikipedia
Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers
for Treating Frontotemporal Dementia
#MMPMID28712747
She A
; Kurtser I
; Reis SA
; Hennig K
; Lai J
; Lang A
; Zhao WN
; Mazitschek R
; Dickerson BC
; Herz J
; Haggarty SJ
Cell Chem Biol
2017[Jul]; 24
(7
): 892-906.e5
PMID28712747
show ga
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.
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