Aberrant Expression of Histone Deacetylases 4 in Cognitive Disorders: Molecular Mechanisms and a Potential Target

Abstract

Histone acetylation is a major mechanism of chromatin remodeling, contributing to epigenetic regulation of gene transcription. Histone deacetylases (HDACs) are involved in both physiological and pathological conditions by regulating the status of histone acetylation. Although histone deacetylase 4 (HDAC4), a member of the HDAC family, may lack HDAC activity, it is actively involved in regulating the transcription of genes involved in synaptic plasticity, neuronal survival, and neurodevelopment by interacting with transcription factors, signal transduction molecules and HDAC3, another member of the HDAC family. HDAC4 is highly expressed in brain and its homeostasis is crucial for the maintenance of cognitive function. Accumulated evidence shows that HDAC4 expression is dysregulated in several brain disorders, including neurodegenerative diseases and mental disorders. Moreover, cognitive impairment is a characteristic feature of these diseases. It indicates that aberrant HDAC4 expression plays a pivotal role in cognitive impairment of these disorders. This review aims to describe the current understanding of HDAC4’s role in the maintenance of cognitive function and its dysregulation in neurodegenerative diseases and mental disorders, discuss underlying molecular mechanisms, and provide an outlook into targeting HDAC4 as a potential therapeutic approach to rescue cognitive impairment in these diseases.

Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes

“…HDAC4 is highly expressed in the human brain, 81 and the subcellular localization of the HDAC4 protein is purportedly modulated by N-methyl-D-aspartate (NMDA) receptors, a specific type of ionotropic glutamate receptor important for controlling synaptic plasticity and memory function 82 . In humans, increased HDAC4 expression is associated with memory deficits 80,82 , which is consistent with the cognitive processing difficulties observed with MD 83,84 . Moreover, drugs that inhibit HDAC4 have antidepressant-like effects on behavior [85][86][87][88] .…”

“…Thus, a deeper understanding of how the serotonergic neural network is formed in the young developing brain may be critical to identifying etiological determinants of MD and other psychiatric conditions. The Histone Deacetylase 4 (HDAC4) gene was altered in MD affected twins, exhibiting increased variation and emerging as part of a genomic region displaying higher mean levels com-pared to MD unaffected twins 80 . HDAC4 is highly expressed in the human brain, 81 and the subcellular localization of the HDAC4 protein is purportedly modulated by N-methyl-D-aspartate (NMDA) receptors, a specific type of ionotropic glutamate receptor important for controlling synaptic plasticity and memory function 82 .…”

Unravelling the GSK3β-related genotypic interaction network influencing hippocampal volume in recurrent major depressive disorder

“…HDAC4 was another gene identified in our study. HDAC4 regulates gene transcription by interacting with transcription factors, signal transduction molecules and HDAC3 to carry out many cellular functions, such as proliferation, differentiation, neuronal survival, and synaptic plasticity (Wu et al, 2016). Hobara et al (2010) reported increased HDAC4 mRNA expression in patients with unipolar and bipolar depression.…”

HDAC4 in ischemic stroke: mechanisms and therapeutic potential

“…According to the sequence homology, HDACs are grouped into class I (HDAC1, 2, 3, and 8), class II (IIa: HDAC4, 5, 7, and 9; IIb: HDAC6 and 10), class III (SIRT1–7), and class IV (HDAC11). The HDAC4 protein consists of a long N-terminal domain and a highly conserved C-terminal catalytic domain [ 15 ]. Compared with most of HDACs, HDAC4 is usually trapped in the cytoplasm.…”

“…In addition, HDACs also have deacetylase-independent functions, including other modifications of histone, such as methylation [ 6 – 8 ]. Importantly, HDACs are dysregulated in a number of brain disorders, which is implicated in the pathogenesis of these diseases, e.g., ischemic stroke, autism, Alzheimer’s disease, and depressive disorders [ 9 – 15 ]. It suggests that HDACs might be potential targets for the treatment of brain disorders.…”