TY - JOUR
T1 - Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia
AU - She, Angela
AU - Kurtser, Iren
AU - Reis, Surya A.
AU - Hennig, Krista
AU - Lai, Jenny
AU - Lang, Audrey
AU - Zhao, Wen Ning
AU - Mazitschek, Ralph
AU - Dickerson, Bradford C.
AU - Herz, Joachim
AU - Haggarty, Stephen J.
N1 - Funding Information:
We are grateful to members of the S.J.H. laboratory and members of the Bluefield Project to Cure Frontotemporal Dementia, Consortium for Frontotemporal Dementia Research, and Tau Consortium for helpful discussions and critical feedback on the manuscript. This research received funding from the Bluefield Project to Cure Frontotemporal Dementia, the National Science Foundation Graduate Research Fellowship Program (A.S.), and the National Institute on Drug Abuse (NIDA) of the NIH (NIH) ( R01DA028301 and R01NS088209 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. S.J.H. is a member of the Scientific Advisory Board of Rodin Therapeutics and is an inventor on HDAC inhibitor-related IP licensed to this entity but not used in this study. S.J.H. is also a member of the Scientific Advisory Board of Frequency Therapeutics and Psy Therapeutics. R.M. is a member of the Scientific Advisory Board and has financial interests in Regenacy Pharmaceuticals, Acetylon Pharmaceuticals, and Frequency Therapeutics. He is also the inventor on IP licensed to these two entities. S.J.H.’s and R.M.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.
Funding Information:
We are grateful to members of the S.J.H. laboratory and members of the Bluefield Project to Cure Frontotemporal Dementia, Consortium for Frontotemporal Dementia Research, and Tau Consortium for helpful discussions and critical feedback on the manuscript. This research received funding from the Bluefield Project to Cure Frontotemporal Dementia, the National Science Foundation Graduate Research Fellowship Program (A.S.), and the National Institute on Drug Abuse (NIDA) of the NIH (NIH) (R01DA028301 and R01NS088209). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. S.J.H. is a member of the Scientific Advisory Board of Rodin Therapeutics and is an inventor on HDAC inhibitor-related IP licensed to this entity but not used in this study. S.J.H. is also a member of the Scientific Advisory Board of Frequency Therapeutics and Psy Therapeutics. R.M. is a member of the Scientific Advisory Board and has financial interests in Regenacy Pharmaceuticals, Acetylon Pharmaceuticals, and Frequency Therapeutics. He is also the inventor on IP licensed to these two entities. S.J.H.’s and R.M.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/7/20
Y1 - 2017/7/20
N2 - 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.
AB - 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.
KW - HDAC inhibitor
KW - chemogenomics
KW - epigenetic regulation
KW - frontotemporal dementia
KW - frontotemporal lobar degeneration
KW - human neuronal culture
KW - optoepigenetic
KW - stem cells
UR - http://www.scopus.com/inward/record.url?scp=85023640339&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85023640339&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2017.06.010
DO - 10.1016/j.chembiol.2017.06.010
M3 - Article
C2 - 28712747
AN - SCOPUS:85023640339
SN - 2451-9456
VL - 24
SP - 892-906.e5
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 7
ER -