The Two Faces of HDAC3: Neuroinflammation in Disease and Neuroprotection in Recovery

Overview

Journal Epigenomics

Specialty Genetics

Date 2024 Nov 8

PMID 39513228

Authors

Cal Rosete

Annie Vogel Ciernia

Affiliations

Soon will be listed here.

Abstract

Histone deacetylase 3 (HDAC3) is a critical regulator of gene expression, influencing a variety of cellular processes in the central nervous system. As such, dysfunction of this enzyme may serve as a key driver in the pathophysiology of various neuropsychiatric disorders and neurodegenerative diseases. HDAC3 plays a crucial role in regulating neuroinflammation, and is now widely recognized as a major contributor to neurological conditions, as well as in promoting neuroprotective recovery following brain injury, hemorrhage and stroke. Emerging evidence suggests that pharmacological inhibition of HDAC3 can mitigate behavioral and neuroimmune deficits in various brain diseases and disorders, offering a promising therapeutic strategy. Understanding HDAC3 in the healthy brain lays the necessary foundation to define and resolve its dysfunction in a disease state. This review explores the mechanisms of HDAC3 in various cell types and its involvement in disease pathology, emphasizing the potential of HDAC3 inhibition to address neuroimmune, gene expression and behavioral deficits in a range of neurodegenerative and neuropsychiatric conditions.

Citing Articles

Histone Deacetylation in Alzheimer's Diseases (AD); Hope or Hype.

Ateya N, Al-Taie S, Jasim S, Uthirapathy S, Chaudhary K, Rani P Cell Biochem Biophys. 2025; .

PMID: 39825060 DOI: 10.1007/s12013-025-01670-0.

References

Ishii S . The Role of Histone Deacetylase 3 Complex in Nuclear Hormone Receptor Action. Int J Mol Sci. 2021; 22(17). PMC: 8431225. DOI: 10.3390/ijms22179138. View

Bohlen C, Bennett F, Tucker A, Collins H, Mulinyawe S, Barres B . Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures. Neuron. 2017; 94(4):759-773.e8. PMC: 5523817. DOI: 10.1016/j.neuron.2017.04.043. View

Mullican S, Gaddis C, Alenghat T, Nair M, Giacomin P, Everett L . Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev. 2011; 25(23):2480-8. PMC: 3243058. DOI: 10.1101/gad.175950.111. View

Li Y, Liu C, Wang G, Wang H, Liu X, Huang C . HDAC3 inhibitor (BRD3308) modulates microglial pyroptosis and neuroinflammation through PPARγ/NLRP3/GSDMD to improve neurological function after intraventricular hemorrhage in mice. Neuropharmacology. 2023; 237:109633. DOI: 10.1016/j.neuropharm.2023.109633. View

Yang L, Chen S, Zhao Q, Pan C, Peng L, Han Y . Histone deacetylase 3 contributes to the antiviral innate immunity of macrophages by interacting with FOXK1 to regulate STAT1/2 transcription. Cell Rep. 2022; 38(4):110302. DOI: 10.1016/j.celrep.2022.110302. View

Tchessalova D, Tronson N . Memory deficits in males and females long after subchronic immune challenge. Neurobiol Learn Mem. 2019; 158:60-72. PMC: 6879099. DOI: 10.1016/j.nlm.2019.01.003. View

Lee D, HAYES J, Pruss D, Wolffe A . A positive role for histone acetylation in transcription factor access to nucleosomal DNA. Cell. 1993; 72(1):73-84. DOI: 10.1016/0092-8674(93)90051-q. View

McNulty S, Barrett R, Vogel-Ciernia A, Malvaez M, Hernandez N, Davatolhagh M . Differential roles for Nr4a1 and Nr4a2 in object location vs. object recognition long-term memory. Learn Mem. 2012; 19(12):588-92. PMC: 3506974. DOI: 10.1101/lm.026385.112. View

Janczura K, Volmar C, Sartor G, Rao S, Ricciardi N, Lambert G . Inhibition of HDAC3 reverses Alzheimer's disease-related pathologies in vitro and in the 3xTg-AD mouse model. Proc Natl Acad Sci U S A. 2018; 115(47):E11148-E11157. PMC: 6255210. DOI: 10.1073/pnas.1805436115. View

10.

Campbell R, Kramar E, Pham L, Beardwood J, Augustynski A, Lopez A . HDAC3 Activity within the Nucleus Accumbens Regulates Cocaine-Induced Plasticity and Behavior in a Cell-Type-Specific Manner. J Neurosci. 2021; 41(13):2814-2827. PMC: 8018887. DOI: 10.1523/JNEUROSCI.2829-20.2021. View

11.

Sominsky L, Walker A, Ong L, Tynan R, Walker F, Hodgson D . Increased microglial activation in the rat brain following neonatal exposure to a bacterial mimetic. Behav Brain Res. 2011; 226(1):351-6. DOI: 10.1016/j.bbr.2011.08.038. View

12.

Shang A, Bylipudi S, Bieszczad K . Inhibition of histone deacetylase 3 via RGFP966 facilitates cortical plasticity underlying unusually accurate auditory associative cue memory for excitatory and inhibitory cue-reward associations. Behav Brain Res. 2018; 356:453-469. DOI: 10.1016/j.bbr.2018.05.036. View

13.

Davis N, Taylor B, Abelleira-Hervas L, Karimian-Marnani N, Aleksynas R, Syed N . Histone deacetylase-3 regulates the expression of the amyloid precursor protein and its inhibition promotes neuroregenerative pathways in Alzheimer's disease models. FASEB J. 2024; 38(10):e23659. DOI: 10.1096/fj.202301762RR. View

14.

He X, Zhang L, Queme L, Liu X, Lu A, Waclaw R . A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration. Nat Med. 2018; 24(3):338-351. PMC: 5908710. DOI: 10.1038/nm.4483. View

15.

Wang Z, Zang C, Cui K, Schones D, Barski A, Peng W . Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell. 2009; 138(5):1019-31. PMC: 2750862. DOI: 10.1016/j.cell.2009.06.049. View

16.

Jiang X, Ye X, Guo W, Lu H, Gao Z . Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation. J Mol Endocrinol. 2014; 53(2):191-200. PMC: 4391273. DOI: 10.1530/JME-14-0066. View

17.

Mutskov V, Gerber D, Angelov D, Ausio J, Workman J, Dimitrov S . Persistent interactions of core histone tails with nucleosomal DNA following acetylation and transcription factor binding. Mol Cell Biol. 1998; 18(11):6293-304. PMC: 109216. DOI: 10.1128/MCB.18.11.6293. View

18.

Euteneuer F, Schwarz M, Hennings A, Riemer S, Stapf T, Selberdinger V . Depression, cytokines and experimental pain: evidence for sex-related association patterns. J Affect Disord. 2010; 131(1-3):143-9. DOI: 10.1016/j.jad.2010.11.017. View

19.

Vashishtha M, Ng C, Yildirim F, Gipson T, Kratter I, Bodai L . Targeting H3K4 trimethylation in Huntington disease. Proc Natl Acad Sci U S A. 2013; 110(32):E3027-36. PMC: 3740882. DOI: 10.1073/pnas.1311323110. View

20.

Zhao Q, Yu Z, Zhang F, Huang L, Xing C, Liu N . HDAC3 inhibition prevents oxygen glucose deprivation/reoxygenation-induced transendothelial permeability by elevating PPARγ activity in vitro. J Neurochem. 2018; 149(2):298-310. DOI: 10.1111/jnc.14619. View