Abstract
Histone deacetylase 3 (HDAC3) plays a crucial role in chromatin remodeling, which, in turn, regulates gene transcription. Hence, HDAC3 has been implicated in various diseases, including ischemic injury, fibrosis, neurodegeneration, infections, and inflammatory conditions. In addition, HDAC3 plays vital roles under physiological conditions by regulating circadian rhythms, metabolism, and development. In this review, we summarize the current knowledge of the physiological functions of HDAC3 and its role in organ injury. We also discuss the therapeutic value of HDAC3 in various diseases.
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Introduction
Solid-organ injury is among the leading causes of death globally and significantly impacts the quality of life. Solid-organ injury can be acute injury occurring in the perioperative period or chronic injury caused by long-term stimulation and toxic insult. Acute injury includes myocardial, cerebral, renal, and hepatic ischemia-reperfusion injury (IRI) [1, 2]. Acute organ injury is characterized by potent proinflammatory responses involving leukocyte migration, cytokine release, microvascular thromboses, and cell death [3,4,5]. The proinflammatory phase of acute injury-associated systemic immune responses is often followed by an immunosuppressive phase [6]. During the pro-inflammatory phase, chemokines and cytokines are secreted by immune cells, and damage-associated molecular patterns (DAMPs) activate pattern recognition receptors (PRRs) [7]. Chronic injury is typically associated with metabolic rewiring, immune imbalance, and tissue remodeling [8, 9]. Most patients with organ injury receive temporary organ support or replacement therapies as there are no specific treatments to reverse or maintain individual organ functions [10]. Therefore, preventive and early supportive interventions are needed.
Epigenetic modifications regulate gene expression and developmental programs in the absence of changes in the gene sequence. Epigenetic modifications include histone modification, DNA methylation, chromosome remodeling, and regulation of transcription or translation by non-coding RNAs [11]. Histone acetylation and deacetylation have been extensively studied in recent years. Histones are intra-nuclear cationic proteins expressed in eukaryotic cells. They modulate gene expression by stabilizing chromatin structure; hence, alterations in histone patterns have been implicated in various diseases [12]. Histone acetylation was first described by Allfrey V in 1964 [13]. By regulating the acetylation of the N-terminal lysine residues of histones, histone acetyltransferases (HATs) and histone deacetylases (HDACs) determine chromatin structure and gene expression (Fig. 1A) [14]. Mounting evidence suggests that HDAC3 plays a key role in solid organ injury [15,16,17]. In this review article, we provide an overview of the current knowledge of the role of HDAC3 in the pathogenesis of solid organ injury, focusing on the possible underlying molecular mechanisms.
A Condensation and relaxation of chromatin due to histone deacetylation and acetylation, respectively. Histone acetylation levels are determined by the interplay between HATs and HDACs. Activation of HDACs leads to a net decrease of histone acetylation, chromatin condensation, and transcriptional repression. Activation of HATs results in a net increase of histone acetylation, chromatin relaxation, and transcriptional activation. B The chemical formula of histone acetylation and deacetylation. C Nuclear receptor co-repressor complexes containing HDAC3, GPS2, TBLX, and TBL1XR bind to nuclear receptors without ligands to induce transcriptional repression via histone deacetylation. D Nuclear receptor-mediated ligand binding inhibits the co-repressor complex and recruits co-activators, facilitating histone acetylation and gene transcription.
HATs and HDACs
Histones are critical components of nucleosomes. Post-translational modifications of histones affect chromatin structure and gene expression [18]. Histones are tightly coiled by DNA to form nucleosomes, contributing to the highly compact packaging of the eukaryotic genome [19]. The positively charged octamers of a linker histone (H1 or H5) and four highly basic histones (H3, H4, H2A, and H2B) interact with the negatively charged DNA via electrostatic bonds. H1 and H5 are responsible for the stabilization of chromosomes, promoting the formation of higher-order structures. Each histone octamer is tightly coiled by 147 base pairs of DNA [20]. These highly compact structures are dynamic and can be regulated by the binding of transcription factors to promoter sequences within the genome [21]. Epigenetic modifications can serve as markers to identify the different types of chromatin. For instance, heterochromatin is characterized by low acetylation levels, whereas euchromatin contains relatively high acetylation levels. Abnormal acetylation of histones may dysregulation gene expression, contributing to the occurrence of diseases [22].
Histone acetylation and deacetylation levels are tightly regulated by the balance between the opposing activities of HATs and HDACs [23]. HATs are divided into three families: Gcn5-related acetyltransferases (GNATs); p300/CREB-binding proteins (CBP); and MOZ, Ybf2/Sas3, Sas2, and Tip60 (MYST)-related HATs. HATs catalyze lysine acetylation of histones by transferring the acetyl-CoA acetyl group to the ε-amino group of the internal lysine residue in the N-terminus. The addition of an acetyl group disrupts the electrostatic interaction between the DNA and histones. By neutralizing the positive lysine charge, histone acetylation alters chromatin structure and gene expression (Fig. 1B) [24, 25]. Deacetylation of histones is usually mediated by HDACs and promotes chromatin condensation and transcriptional repression [23]. In mammals, HDACs are divided into four categories: class I, II, III, and IV. Class I HDACs include HDAC1, HDAC2, HDAC3, and HDAC8. These HDACs are predominately found in the nucleus, but HDAC3 can translocate from the nucleus into the cytosol [26]. Class II HDACs include IIa HDACs (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb HDACs (HDAC6 and HDAC10). Class IIa HDACs can shuttle between the nucleus and the cytosol. Class III HDACs are also known as sirtuins because of their homology to the yeast HDAC Sir2; this class includes SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7. Class IV HDACs only includes one member (HDAC11), which is predominantly expressed in the nucleus (Fig. 2). Class III HDACs are NAD-dependent enzymes, whereas the other HDACs are zinc-dependent enzymes [27, 28].
Class I, IIA, VI, and part of class III HDACs are mainly found in the nucleus. HDAC3, HDAC4, HDAC7, HDAC9, SIRT1, and SIRT2 shuffle between the nucleus and cytoplasm. Class IIB HDACs, including HDAC6 and HDAC10, are localized in the cytoplasm. Class III HDACs, including SIRT3, SIRT4, and SIRT5, are localized in mitochondria.
Structure and function of HDAC3
The unique structure of HDAC3
All class I HDAC members except HDAC8 share a similar structure, especially near the substrate-binding site [29]. Structural differences also exist between HDAC3 and other class I HDACs. HDAC3 possesses an aspartate residue at position 92, whereas HDAC1 and HDAC2 have a glutamate residue at this position at the outer rim of the cavity. Furthermore, HDAC1 and HDAC2 have a tyrosine residue at position 199, whereas HDAC3 has phenylalanine. Particularly, position 107 of HDAC3 is a tyrosine, while in the same position of HDAC1/2 is serine. Tyrosine 107 of HDAC3 leads to steric hindrance for binding to the foot pocket, precluding the binding of larger functional groups to inhibitors. Based on these differences, selective inhibitors against HDAC1, HDAC2, and HDAC3 can be designed [30, 31]. Hydrophobic amino acids at positions 13 and 29 of HDAC3 also differ from those in HADC1 and HDAC2, enabling the development of selective inhibitors targeting the foot pocket [32]. The biological function of HDAC3 requires nuclear receptor co-repressors, including silencing mediator of retinoic acid and thyroid hormone receptor (SMRT or NCoR2) and nuclear receptor co-repressor 1 (NCoR1) [33, 34]. Theoretically, the members involving 1, 2, 3, and 8 in the class I HDAC family may share similar functions and other members of the class I HDAC family will compensate when HDAC3 is knocked out effect. However, previous studies demonstrated that the expression of HDAC3 is not in accordance with HDAC1, HDAC2, and HDAC8 in the context of different pathological stimuli. Meanwhile, other members also display different biological functions from HDAC3 [35,36,37]. Therefore, we speculate that the other members in class I HDAC will not compensate when HDAC3 is absent based on the published articles. Of course, the expression of HDAC1, 2 and 8 should be also detected when HDAC3 was silenced in future studies.
Enzymatic activity and non-enzymatic functions of HDAC3
Nuclear receptors act as genetic switches regulating gene transcription by activating signal-dependent transcription factors. In turn, transcription factors integrate hormonal, metabolic, and environmental cues, recruiting various co-repressors and co-activators to specific genomic sequences [38]. HDAC3-containing nuclear receptor co-repressor complexes, including NCoR and SMRT, bind to ligand-free nuclear receptors, which directly repress gene expression. NCoR and SMRT complexes contain WD40 repeat-containing proteins, such as TBL1XR1 and TBL1X (Fig. 1C). These complexes recruit the 19S proteasome and the ubiquitylation machinery to histones [39]. G-protein pathway suppressor 2 (GPS2) is another core element of NCoR and SMRT complexes [40]; however, the role of GPS2 remains unclear. Noteworthily, under certain circumstances, HDAC3 indirectly activates gene expression. By contrast, nuclear receptor-mediated ligand binding inactivates the co-repressor complex and recruits co-activators, thereby facilitating gene transcription via histone acetylation [41] (Fig. 1D).
Enzymatic activity
The catalytic function of HDAC3 requires the physical interaction between HDAC3 and the deacetylase-activating domain (DAD) of NCoR and SMRT proteins. Crystal structure analysis of these complexes unveiled that abundant protein-protein interactions between the N-terminus of HDAC3 and the DAD of SMRT. Inositol tetraphosphate (Ins[1,4,5,6]P4 or IP4) has been identified, acting as “intermolecular glue” enhancing the interaction between HDAC3 and SMRT DAD via salt bridges and hydrogen bonds [42]. Intriguingly, once HDAC3 is dissociated from the NCoR or SMRT complex, it becomes unstable and is sequestered into a TCP1-ring complex in the cytoplasm [43]. TCP1 promotes HDAC3 folding in the cytoplasm, facilitating the formation of NCoR or SMRT complex containing an active HDAC3 enzyme in an ATP-dependent manner [44].
Non-enzymatic activity
In addition to its enzymatic functions, HDAC3 also displays non-enzymatic activities. Point mutations in Y298F, one of the active sites of HDAC3, disrupt its deacetylase activity. In the livers of HDAC3-deficient mice, the mutant HDAC3 can partially rescue hepatosteatosis and inhibit the expression of lipogenic genes, suggesting that HDAC3 has non-enzymatic functions [44]. Moreover, global HDAC3 knockout may lead to embryonic lethality because of gastrulation defects [45]. However, mutations in the DAD of SMRT and NCoR did not affect the Mendelian ratios of offspring mice, although the mice showed little HDAC3 enzymatic activity [45, 46]. Indeed, approximately 10% of enzymes with inactivating mutations in their active site are conserved in mammals, further supporting their non-catalytic functions [47]. Therefore, the non-enzymatic functions of HDAC3 should be taken into account in the development of HDAC3 inhibitors.
Physiological functions of HDAC3
Several genetically engineered mice with cell type-specific deletion of the Hdac3 gene have been developed recently to investigate the role of HDAC3. Notably, HDAC3 has been shown to regulate metabolism by increasing fatty acid oxidation and enhancing circadian histone deacetylation [47, 48]. HDAC3 also inhibits white adipose tissue metabolism by enhancing the futile cycle of fatty acid synthesis and oxidation and by decreasing acetylation in the enhancers of Ucp1 and Ppar-γ [48]. In addition, HDAC3 is essential for the development of vital organs. For example, mice with lung endodermal epithelium-specific Hdac3 knockout displayed lethality 2 to 10 days after birth due to defects in lung sacculation and early alveologenesis [49]. Similarly, cardiac progenitor cell-specific Hdac3 knockout led to ventricular septal defects and underdevelopment of ventricular walls, causing embryonic lethality [46]. Apart from lung and heart development, HDAC3 is also essential for the development and remodeling of bones [50].
Moreover, HDAC3 contributes to the maintenance of intestinal homeostasis and host defense. Notably, HDAC3 loss can cause inflammation and intestinal damage [50]. Furthermore, HDAC3-deficiency in neural progenitor cells impaired cortical lamination and neuronal migration, resulting in death within 16 h after birth. The critical role of HDAC3 in neuronal cell fate and function may be associated with HDAC3-mediated expression of T-box brain protein 1 [51]. Based on these findings, we conclude that HDAC3 expression and function are essential for multiple aspects of mammalian physiology and homeostasis (Fig. 3). The role of HDAC3 in organ injury is described below (Table 1).
Under physiological condition, HDAC3 is mainly responsible for the development and homeostasis of liver, heart, brain, lung, bone, pancreas, intestine, and adipocyte. However, the abnormal expression of HDAC3 also contributes to organ injury including heart, brain, pancreas, kidney, lung, and liver.
The emerging roles of HDAC3 in solid organ injury
Brain
Ischemic stroke is a potentially deadly cardiovascular disease causing significant morbidity and mortality worldwide. Ischemic stroke is usually triggered by the thrombus in the cerebral vasculature. Persistent occlusion in cerebral vasculature may hinder the supply of oxygen and glucose in the local brain tissue, eventually causing neuroinflammation, neuronal cell death, and secondary tissue injury during cerebral hypoperfusion and reperfusion [52, 53]. Type-1 interferons (IFNs) are pleiotropic cytokines regulating the expression of proinflammatory genes and orchestrating innate immune responses [54]. Hence, targeting IFNs or their upstream regulators may help prevent occlusion-induced brain injury [55, 56]. The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key regulator of the IFN pathway and innate immunity in response to double-stranded DNA (dsDNA) [57]. Microglia are innate immune cells residing in the central nervous system and serve as the principal effector cells contributing to neuroinflammation and brain injury caused by IRI. Conditional knockout of cGAS in microglia significantly relieved cerebral IRI. Mice with microglia-specific deletion of Hdac3 displayed low expression of cGAS at the mRNA and protein levels, as well as decreased levels of STING and IFN-γ. Mechanistically, HDAC3 deacetylates p65 at K122 and promotes the nuclear accumulation of p65, which regulates the transcription of cGAS [37]. HDAC3 inhibition using RGFP966 dampened the activation of melanoma 2 (AIM2) inflammasome in microglia, preventing ischemic brain injury [120]. As all class I HDACs have a zinc ion in the active site, small molecule inhibitors typically possess the same zinc-binding group. In addition, most HDAC inhibitors possess a linker connecting the zinc-binding group to a cap** group to mimic the lysine alkyl side chain. The most well-known zinc-binding group involves o-aminoanilides and hydroxamic acids. Entinostat (MS-275) and other selective class I inhibitors are based on o-aminoanilides. The selective HDAC3 inhibitor RGFP966 was developed through the modification of o-aminoanilides. PD106 and BRD3308 are also selective HDAC3 inhibitors used for the treatment of Friedreich’s ataxia, diabetes mellitus, and HIV infection [121]. Considering the potential of the o-aminoanilide scaffold in the development of selective HDAC3 inhibitors, many derivatives were synthesized based on this scaffold. In addition, some natural compounds can also regulate the expression or activity of HDAC3, exerting protective effects in various diseases in animal and cell models. For instance, juglanin prevents high-fat diet-induced renal injury by blocking the nuclear translocation of HDAC3 and NF-κB and thereby inhibiting inflammation and dyslipidemia [122]. miRNAs also play critical roles in nerve injury by targeting HDAC3 [123, 124]. The most common HDAC3 inhibitors and their roles in solid organ injury are summarized in Table 2. Most of the synthesized HDAC3 inhibitors lack specificity, as they partly inhibit other HDACs because of the high structural similarity of HDACs. Nearly all selective HDAC3 inhibitors are o-aminoanilide derivatives, the selectivity of which is mainly accessed through testing their IC50s [125]. However, this test method is not accurate. Alternatively, the Ki value of the o-aminoanilides can be determined by testing the kon and koff values of the inhibitors directly.
To build up a better picture of the regulatory mechanism of HDAC3, the activation mechanism of HDAC3 should also be paid particular attention. To our knowledge, there are mainly 3 aspects to promote the expression or the activity of HDAC3 at present. On the one hand, HDAC3 could be transcriptionally activated by certain transcription factors including Smad3 including Smad3 through directly binding its promoter [89]. On the other hand, HDAC3 activity could be enhanced via deubiquitinating. For example, HDAC3 activity could be enhanced by ubiquitin-specific protease 38 (USP38) via deubiquitinating. Notably, USP38 knockdown and overexpression could not change the protein level of HDAC3 [126]. In addition, PIWIL2 can also interact with HDAC3, giving rise to the stabilization of HDAC3 from ubiquitin-mediated degradation via competitive relation with E3 ubiquitin ligase Siah2. Meanwhile, PIWIL2 facilitated the interaction between CK2α and HDAC3, thus enhancing HDAC3 activity (Doi: 10.1038/s41419-018-0462-8). Last but not least, the microbiota-derived metabolite [inositol-1,4,5-trisphosphate (InsP3)] could promote epithelial repair by promoting HDAC3 activity, but the detailed mechanism remains unclear [127].
Clinical value of HDAC3
Till now, a great many clinical studies have also established the clinical position of HDAC3 in solid organ injury. For instance, compared with normal-weight women, obese individuals owned reduced levels of HDAC1, HDAC3, as well as HDAC9 in adipose tissues. Meanwhile, the mRNA levels and activity of these HDACs displayed an inverse correlation with inflammatory markers, obesity indices, and insulin levels, indicating that these HDACs have adverse effects on the development of obesity and diabetes mellitus [128]. One Chinese case-control study also demonstrated that the single nucleotide polymorphism of HDAC3 including rs11741808, rs2547547, and rs2547547 polymorphism was related to type 2 diabetes mellitus [129]. And combined HDAC3 and HDAC9 genes with diabetes mellitus worsen atherosclerosis and resulted in stroke [130, 131]. These clinical studies suggested that the genetic change of HDAC3 is closely associated with the development of diabetes mellitus and cerebrovascular disease. However, few clinical studies have reported the roles of HDAC3 in other types of solid organ injury. Before we reach clinical attempts, we might have to obtain more clinical data on HDAC3 to comprehensively harness the knowledge to benefit humans.
Future perspective and conclusion
HDAC3 is a unique and important member of the HDAC family. The catalytic activity of HDAC3 mainly depends on the integrity of nuclear receptor co-repressor complexes. In this review, we summarized the enzymatic and non-enzymatic functions of HDCA3. The non-enzymatic functions of HDAC3 should be taken into consideration when develo** new HDAC3-targeting strategies. We also briefly discussed the role of HDAC3 in the integration of various signals from the environment to regulate cellular fate, development, metabolism, and energy homeostasis. We also described the role of HDAC3 in the injury of solid organs, including the brain, heart, kidneys, liver, lungs, and pancreas. Although HDAC3 is beneficial under physiological conditions, pathological HDAC3 upregulation is detrimental in the pathogenesis of solid organ injury.
No human disease-causing mutations have been identified in the HDAC3 gene thus far, possible because germline mutations in HDAC3 may be may embryonically lethal in humans. However, numerous single-nucleotide polymorphisms (SNPs) in HDAC3 genes have been reported [130, 132]. We speculate that some SNPs may lie within enhancers and that these SNPs may hinder the recruitment of HDAC3 because of impaired binding of nuclear receptors or transcription factors, dysregulating HDAC3 expression. Another glaring question is how to overcome the high structural similarity of zinc-dependent HDAC isoenzymes to develop specific HDAC3 inhibitors rather than pan-HDAC inhibitors. The biological functions of HDAC3 should also be further explored in future studies.
Facts
Epigenetic modifications could regulate gene activity, as well as the development of an organism without changing gene sequence.
The reversible acetylation on the N-terminal lysine residues of histone proteins by histone HATs and histone deacetylases HDACs synergistically determine chromatin structure and gene expression.
HDAC3 is closely correlated with acute/chronic injury in the brain, heart, kidney, liver, lung, and pancreas.
Open questions
What is the physiological function of HDAC3 in development and homeostasis?
What are the precise molecular mechanisms of HDAC3 in solid organ injury?
What are the current situations and challenges in develo** novel drugs targeting HDAC3 for solid organ injury?
Data availability
No applicable resources were generated or analyzed during this study.
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This work was supported by grants from the National Natural Science Foundation of China (No. 81800343, 81770095, 81700093).
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LN was responsible for conceiving and designing the review and writing the manuscript. XR was in charge of conceiving and designing some portions of the review and writing the manuscript. WB reviewed and edited the manuscript and served as the corresponding author. GQ was the principal investigator of this study and served as the corresponding author.
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Ning, L., Rui, X., Bo, W. et al. The critical roles of histone deacetylase 3 in the pathogenesis of solid organ injury. Cell Death Dis 12, 734 (2021). https://doi.org/10.1038/s41419-021-04019-6
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DOI: https://doi.org/10.1038/s41419-021-04019-6
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