Contribution of histone acetylation to the serotonin-mediated long-term synaptic plasticity in terrestrial snails.

Serotonin plays a decisive role in long-term synaptic plasticity and long-term memory in mollusks. Previously, we demonstrated that histone acetylation is a regulatory mechanism of long-term memory in terrestrial snail. At the behavioral level, many studies were done in Helix to elucidate the role of histone acetylation and serotonin. However, the impact of histone acetylation on long-term potentiation of synaptic efficiency in electrophysiological studies in Helix has been studied only in one paper. Here we investigated effects of serotonin, histone deacetylases inhibitors sodium butyrate and trichostatin A, and a serotonergic receptor inhibitor methiothepin on long-term potentiation of synaptic responses in vitro. We demonstrated that methiothepin drastically declined the EPSPs amplitudes when long-term potentiation was induced, while co-application either of histone deacetylase inhibitors sodium butyrate or trichostatin A with methiothepin prevented the weakening of potentiation. We showed that single serotonin application in combination with histone deacetylase blockade could mimic the effect of repeated serotonin applications and be enough for sustained long-lasting synaptic changes. The data obtained demonstrated that histone deacetylases blockade ameliorated deficits in synaptic plasticity induced by different paradigms (methiothepin treatment, the weak training protocol with single application of serotonin), suggesting that histone acetylation contributes to the serotonin-mediated synaptic plasticity.

The histone deacetylase Hdac7 supports LPS-inducible glycolysis and Il-1ß production in murine macrophages via distinct mechanisms.

TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both TLR-inducible glycolysis and inflammatory responses. Here, we show that the TLR4 agonist LPS, as well as agonists of other TLRs, rapidly increase enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this specific lysine deacetylase during immediate macrophage activation. With the exception of the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate, was attenuated in Hdac7-deficient mouse macrophages responding to submaximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1ß and Ccl2. Thus, Hdac7 enzymatic activity is required for TLR-inducible production of specific inflammatory mediators, whereas it acts in an enzyme-independent fashion to reprogram metabolism in macrophages responding to submaximal LPS concentrations. Hdac7 is thus a bifurcation point for regulated metabolism and inflammatory responses in macrophages. Taken together with existing literature, our findings support a model in which submaximal and maximal activation of macrophages via TLR4 instruct glycolysis through distinct mechanisms, leading to divergent biological responses.

Inhibition of histone deacetylase 5 ameliorates abnormalities in 16p11.2 duplication mouse model.

Microduplication of the human 16p11.2 gene locus is associated with a range of neurodevelopmental outcomes, including autism spectrum disorder (ASD). Mice carrying heterozygous 16p11.2 duplication (16p11.2dp/+) display social deficits, which is attributable to impaired GABAergic synaptic function in prefrontal cortex (PFC) driven by downregulation of Npas4, an activity-dependent transcription factor that regulates GABA synapse formation. However, the molecular mechanisms underlying the diminished transcription of Npas4 in 16p11.2 duplication remain unknown. Npas4 is one of the target genes regulated by histone deacetylase 5 (HDAC5), an epigenetic enzyme repressing gene expression via removal of transcription-permissive acetyl groups from histones. Here we report that HDAC5 expression is elevated and histone acetylation is reduced at the Npas4 promoter in PFC of 16p11.2dp/+ mice. Treatment with the HDAC5 inhibitor LMK235 normalizes histone acetylation, restores GABAergic signaling in PFC, and significantly improves social preference in 16p11.2dp/+ mice. These findings suggest that HDAC5 inhibition is a promising therapeutic avenue to alleviate genetic, synaptic and behavioral deficits in 16p11.2 duplication conditions.

Class I HDAC modulates angiotensin II-induced fibroblast migration and mitochondrial overactivity.

BACKGROUND: Inhibition of histone deacetylases (HDACs) attenuates cardiac fibrosis. In this study, we evaluated whether the inhibition of class I HDACs can attenuate angiotensin II (ANG II)-induced fibrogenesis and mitochondrial malfunction through its effects on reactive oxygen species (ROS) and calcium dysregulation in human cardiac fibroblasts (CFs). METHODS: Seahorse XF24 extracellular flux analyser, fluorescence staining, Western blotting, HDAC activity assays and Transwell migration assay were used to study mitochondrial respiration, adenosine triphosphate (ATP) production, mitochondrial calcium uptake and ROS, HDAC expression and activity and fibroblast activity in CFs without (control) or with ANG II (100 nM) and/or MS-275 (HDAC class 1 inhibitor, 10 µM) for 24 h. RESULTS: ANG II increased HDAC activity without changing protein expression in CFs. Compared with controls, ANG II-treated CFs had greater migration activity, higher ATP production, maximal respiration and spare capacity with higher mitochondrial Ca2+ uptake and ROS generation, which was attenuated by the administration of MS-275. ANG II activated CFs by increasing mitochondrial calcium content and ATP production, which may be caused by increased HDAC activity. Inhibition of HDAC1 attenuated the effects of ANG II by reducing mitochondrial ROS generation and calcium overload. CONCLUSIONS: Modulating mitochondrial function by regulation of HDAC may be a novel strategy for controlling CF activity.

Histone deacetylase 3 suppresses the expression of SHP-1 via deacetylation of DNMT1 to promote heart failure.

AIMS: Heart failure (HF) is a progressive disease with recurrent hospitalizations and high mortality. However, the mechanisms underlying HF remain unclear. The present study aimed to explore the regulatory mechanism of histone deacetylase 3 (HDAC3) and DNA methyltransferase 1 (DNMT1)/Src homology domain 2-containing tyrosine phosphatase-1 (SHP-1) axis in HF. METHODS: The HF rat models and hypertrophy cell models were established. The characteristic parameters of the heart were detected by echocardiography. A multichannel physiological signal acquisition system was used to detect the hemodynamic parameters. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of HDAC3, DNMT1, and SHP-1 mRNAs, while Western blot was applied to analyze the expression of proteins. Masson staining was used to analyze the degree of collagen fiber infiltration. TdT-mediated DUTP nick end labeling (TUNEL) staining was performed to analyze the apoptosis of myocardial tissue cells. Co-immunoprecipitation (co-IP) was conducted to study the interaction between HDAC3 and DNMT1. Flow cytometry was used to analyze the apoptosis. KEY FINDINGS: HDAC3 and DNMT1 were highly expressed in HF rat and hypertrophy cell models. HDAC3 modified DNMT1 through deacetylation to inhibit ubiquitination-mediated degradation, which promoted the expression of DNMT1. DNMT1 inhibited SHP-1 expression via methylation in the promoter region. In summary, HDAC3 modified DNMT1 by deacetylation to suppress SHP-1 expression, which in turn led to the development of cardiomyocyte hypertrophy-induced HF. SIGNIFICANCE: This study provided potential therapeutic targets for HF treatment.

Repression of HDAC5 by acetate restores hypothalamic-pituitary-ovarian function in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) accounts for 90-95 % of worldwide diabetes cases and is primarily characterized by insulin resistance. Its progression as a chronic metabolic disease has been largely associated with female reproductive abnormalities, including ovarian dysfunction with consequent infertility. Epigenetic modifications have been suggested as a possible link to metabolic comorbidities. We therefore hypothesized that short chain fatty acids, acetate (ACA), a potential histone deacetylase inhibitor (HDAC) ameliorates hypothalamic-pituitary-ovarian (HPO) dysfunction in T2DM. Female Wistar rats weighing 160-190 g were allotted into three groups (n = 6/group): Control (vehicle; po), T2D and T2D + ACA (200 mg/kg; po). T2DM was induced by fructose administration (10 %; w/v) for 6 weeks and single dose of streptozotocin (35 mg/kg; ip). The present data showed that in addition to insulin resistance, increased fasting blood glucose and insulin, T2DM induced elevated plasma, hypothalamic and ovarian triglyceride, lipid peroxidation, TNF-α and glutathione depletion. Aside, T2DM also led to increased plasma lactate production and γ-Glutamyl transferase as well as decreased gonadotropins/17ß-estradiol. Histologically, hypothalamus, pituitary and ovaries revealed disrupted neuronal cells/moderate hemorrhage, altered morphology/vascular congestions, and degenerated antral follicle/graafian follicle with mild fibrosis and infiltrated inflammatory cells respectively in T2D animals. Interestingly, these alterations were accompanied by elevated plasma/hypothalamic HDAC5 and attenuated when treated with acetate. The present results demonstrate that T2DM induces HPO dysfunction, which is accompanied by elevated circulating/hypothalamic HDAC5. The results in addition suggest that acetate restores HPO function in T2DM by suppression of HDAC5 and enhancement of insulin sensitivity.

The contributory roles of histone deacetylases (HDACs) in hematopoiesis regulation and possibilities for pharmacologic interventions in hematologic malignancies.

Although the definitive role of epigenetic modulations in a wide range of hematologic malignancies, spanning from leukemia to lymphoma and multiple myeloma, has been evidenced, few articles reviewed the task. Given the high accessibility of histone deacetylase (HDACs) to necessary transcription factors involved in hematopoiesis, this review aims to outline physiologic impacts of these enzymes in normal hematopoiesis, and also to outline the original data obtained from international research laboratories on their regulatory role in the differentiation and maturation of different hematopoietic lineages. Questions on how aberrant expression of HDACs contributes to the formation of hematologic malignancies are also responded, because these classes of enzymes have a respectable share in the development, progression, and recurrence of leukemia, lymphoma, and multiple myeloma. The last section provides a special focus on the therapeutic perspectiveof HDACs inhibitors, either as single agents or in a combined-modal strategy, in these neoplasms. In conclusion, optimizing the dose and the design of more patient-tailored inhibitors, while maintaining low toxicity against normal cells, will help improve clinical outcomes of HDAC inhibitors in hematologic malignancies.

AtHDA6 functions as an H3K18ac eraser to maintain pericentromeric CHG methylation in Arabidopsis thaliana.

Pericentromeric DNA, consisting of high-copy-number tandem repeats and transposable elements, is normally silenced through DNA methylation and histone modifications to maintain chromosomal integrity and stability. Although histone deacetylase 6 (HDA6) has been known to participate in pericentromeric silencing, the mechanism is still yet unclear. Here, using whole genome bisulfite sequencing (WGBS) and chromatin immunoprecipitation-sequencing (ChIP-Seq), we mapped the genome-wide patterns of differential DNA methylation and histone H3 lysine 18 acetylation (H3K18ac) in wild-type and hda6 mutant strains. Results show pericentromeric CHG hypomethylation in hda6 mutants was mediated by DNA demethylases, not by DNA methyltransferases as previously thought. DNA demethylases can recognize H3K18ac mark and then be recruited to the chromatin. Using biochemical assays, we found that HDA6 could function as an 'eraser' enzyme for H3K18ac mark to prevent DNA demethylation. Oxford Nanopore Technology Direct RNA Sequencing (ONT DRS) also revealed that hda6 mutants with H3K18ac accumulation and CHG hypomethylation were shown to have transcriptionally active pericentromeric DNA.

Histone Deacetylase 4 Controls Extracellular Matrix Production in Orbital Fibroblasts from Graves' Ophthalmopathy Patients.

Background: Graves' ophthalmopathy (GO) is an autoimmune eye disease with the characteristic symptoms of eyelid retraction and proptosis. Orbital fibroblast activation induced by platelet-derived growth factor-BB (PDGF-BB) stimulation plays a crucial role in GO pathogenesis, leading to excessive proliferation and extracellular matrix production by orbital fibroblasts. Currently, GO treatment options remain limited and novel therapies including targeted drugs are needed. Histone deacetylases (HDACs) are associated with the development and progression of several cancers and autoimmune diseases by epigenetically controlling gene transcription, and HDAC inhibitors (HDACis) may have therapeutic potential. Nevertheless, the role of HDACs in orbital fibroblasts from GO is unknown. Therefore, we studied the expression of HDACs as well as their contribution to extracellular matrix production in orbital fibroblasts. Methods: Orbital tissues were obtained from GO patients (n = 18) who underwent decompression surgery with approval from the Institutional Review Board of the Faculty of Medicine (Protocol number 401/61), Chulalongkorn University (Bangkok, Thailand). Furthermore, orbital tissue was obtained from control patients (n = 3) without inflammatory or thyroid disease who underwent surgery for cosmetic reasons. Orbital fibroblast cultures were established from the orbital tissues. HDAC mRNA and protein expression in orbital fibroblasts was analyzed by reverse transcription-quantitative real-time PCR and Western blot. PDGF-BB-activated orbital fibroblast and orbital tissues were treated with HDACis or HDAC4 small-interfering RNA. Results: PDGF-BB-stimulated orbital fibroblasts had upregulated HDAC4 mRNA and protein expression. HDAC4 mRNA expression was significantly higher in GO compared with healthy control orbital fibroblasts. Histone H3 lysine 9 acetylation (H3K9ac) decreased upon PDGF-BB stimulation. Treatment with HDAC4i (tasquinimod) and HDAC4/5i (LMK-235) significantly decreased both proliferation and hyaluronan production in PDGF-BB-stimulated orbital fibroblasts. HDAC4 silencing reduced mRNA expression of hyaluronan synthase 2 (HAS2), collagen type I alpha 1 chain (COL1A1), Ki67, and α-smooth muscle actin (α-SMA), as well as hyaluronan production in PDGF-BB-stimulated orbital fibroblasts. Tasquinimod significantly reduced HAS2 and α-SMA mRNA expression in whole orbital tissue. Conclusion: Our data indicated, for the first time, that altered HDAC4 regulation along with H3K9 hypoacetylation might represent a mechanism that contributes to excessive proliferation and extracellular matrix production by orbital fibroblasts in GO. HDAC4 might represent a novel target for GO therapy.

Histone deacetylase 9 deficiency exaggerates uterine M2 macrophage polarization.

The maternal-foetal interface is an immune-privileged site where the semi-allogeneic embryo is protected from attacks by the maternal immune system. Uterine macrophages are key players in establishing and maintaining pregnancy, and the dysregulation of the M1-M2 subpopulation balance causes abortion. We separated two distinct mouse uterine macrophage subpopulations during early pregnancy, CD45+ F4/80+ CD206- M1-like (M1) and CD45+ F4/80+ CD206+ M2-like (M2) cells. The M1 preponderance was significantly exaggerated at 6 hours after lipopolysaccharide (LPS) treatment, and adoptive transfer of M2 macrophages partially rescued LPS-induced abortion. RNA sequencing analysis of mouse uterine M2 versus M1 revealed 1837 differentially expressed genes (DEGs), among which 629 was up-regulated and 1208 was down-regulated. Histone deacetylase 9 (Hdac9) was one of the DEGs and validated to be significantly up-regulated in uterine M2 as compared with M1. Remarkably, this differential expression profile between M1 and M2 was also evident in primary splenic macrophages and in vitro polarized murine peritoneal, bone marrow-derived and RAW 264.7 macrophages. In Hdac9/HDAC9 knockout RAW 264.7 and human THP-1-derived macrophages, the expression of M1 differentiation markers was unchanged or decreased whereas M2 markers were increased compared with the wild-type cells, and these effects were unrelated to compromised proliferation. Furthermore, Hdac9/HDAC9 ablation significantly enhanced the phagocytosis of fluorescent microspheres in M2 Raw 264.7 cells yet decreased the capacity of THP-1-derived M1 macrophages. The above results demonstrate that Hdac9/HDAC9 deficiency exaggerates M2 macrophage polarization in mouse and human macrophages, which may provide clues for our understanding of the epigenetic regulation on macrophage M1/M2 polarization in maternal-foetal tolerance.

Functional interplay of histone lysine 2-hydroxyisobutyrylation and acetylation in Arabidopsis under dark-induced starvation.

Lysine 2-hydroxyisobutyrylation (Khib) is a novel type of histone acylation whose prevalence and function in plants remain unclear. Here, we identified 41 Khib sites on histones in Arabidopsis thaliana, which did not overlap with frequently modified N-tail lysines (e.g. H3K4, H3K9 and H4K8). Chromatin immunoprecipitation-sequencing (ChIP-seq) assays revealed histone Khib in 35% of protein-coding genes. Most Khib peaks were located in genic regions, and they were highly enriched at the transcription start sites. Histone Khib is highly correlated with acetylation (ac), particularly H3K23ac, which it largely resembles in its genomic and genic distribution. Notably, co-enrichment of histone Khib and H3K23ac correlates with high gene expression levels. Metabolic profiling, transcriptome analyses, and ChIP-qPCR revealed that histone Khib and H3K23ac are co-enriched on genes involved in starch and sucrose metabolism, pentose and glucuronate interconversions, and phenylpropanoid biosynthesis, and help fine-tune plant response to dark-induced starvation. These findings suggest that Khib and H3K23ac may act in concert to promote high levels of gene transcription and regulate cellular metabolism to facilitate plant adaption to stress. Finally, HDA6 and HDA9 are involved in removing histone Khib. Our findings reveal Khib as a conserved yet unique plant histone mark acting with lysine acetylation in transcription-associated epigenomic processes.

Trichostatin A promotes esophageal squamous cell carcinoma cell migration and EMT through BRD4/ERK1/2-dependent pathway.

BACKGROUND: Histone deacetylases (HDACs) have been demonstrated to be aberrantly activated in tumorigenesis and cancer development. Thus, HDAC inhibitors (HDACIs) are considered to be promising anti-cancer therapeutics. However, recent studies have shown that HDACIs promote the migration of many cancer cells. Therefore, there is a need to elucidate the underlying mechanisms of HDACIs on cancer cell migration to establish a combination therapy that overcomes HDACI-induced cell migration. METHODS: KYSE-150 and EC9706 cells were treated differently. Effects of drugs and siRNA treatment on tumor cell migration and cell signaling pathways were investigated by transwell migration assy. Gene expression for SNAI2 was tested by RT-qPCR. Western blot analysis was employed to detect the level of E-cadherin, ß-catenin, vimentin,Slug，ERK1/2, H3, PAI-1 and BRD4. The effect of drugs on cell morphology was evaluated through phase-contrast microscopic images. RESULTS: TSA promotes epithelial-mesenchymal transition (EMT) in ESCC cells by downregulating the epithelial marker E-cadherin and upregulating mesenchymal markers ß-catenin, vimentin, Slug, and PAI-1. Knockdown of Slug by siRNA or inhibition of PAI-1 clearly suppressed TSA-induced ESCC cell migration and resulted in the reversal of TSA-triggered E-cadherin, ß-catenin, and vimentin expression. However, no crosstalk between Slug and PAI-1 was observed in TSA-treated ESCC cells. Blocking ERK1/2 activation also inhibited TSA-induced ESCC cell migration, EMT, and upregulation of Slug and PAI-1 levels in ESCC cells. Interestingly, inhibition of BRD4 suppressed TSA-induced ESCC cell migration and attenuated TSA-induced ERK1/2 activation and upregulation of Slug and PAI-1 levels. CONCLUSIONS: Our data indicate the existence of at least two separable ERK1/2-dependent signaling pathways in TSA-mediated ESCC cell migration: an ERK1/2-Slug branch and an ERK1/2-PAI-1 branch. Both branches of TSA-induced ESCC cell migration appear to favor the EMT process, while BRD4 is responsible for two separable ERK1/2-dependent signaling pathways in TSA-mediated ESCC cell migration.

HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis.

The transition from meiotic spermatocytes to postmeiotic haploid germ cells constitutes an essential step in spermatogenesis. The epigenomic regulatory mechanisms underlying this transition remain unclear. Here, we find a prominent transcriptomic switch from the late spermatocytes to the early round spermatids during the meiotic-to-postmeiotic transition, which is associated with robust histone acetylation changes across the genome. Among histone deacetylases (HDACs) and acetyltransferases, we find that HDAC3 is selectively expressed in the late meiotic and early haploid stages. Three independent mouse lines with the testis-specific knockout of HDAC3 show infertility and defects in meiotic exit with an arrest at the late stage of meiosis or early stage of round spermatids. Stage-specific RNA-seq and histone acetylation ChIP-seq analyses reveal that HDAC3 represses meiotic/spermatogonial genes and activates postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations. Unexpectedly, abolishing HDAC3 catalytic activity by missense mutations in the nuclear receptor corepressor (NCOR or SMRT) does not cause infertility, despite causing histone hyperacetylation as HDAC3 knockout, demonstrating that HDAC3 enzyme activity is not required for spermatogenesis. Motif analysis of the HDAC3 cistrome in the testes identified SOX30, which has a similar spatiotemporal expression pattern as HDAC3 during spermatogenesis. Depletion of SOX30 in the testes abolishes the genomic recruitment of the HDAC3 to the binding sites. Collectively, these results establish the SOX30/HDAC3 signaling as a key regulator of the transcriptional program in a deacetylase-independent manner during the meiotic-to-postmeiotic transition in spermatogenesis.

The role of microRNAs in the osteogenic and chondrogenic differentiation of mesenchymal stem cells and bone pathologies.

Mesenchymal stem cells (MSCs) have been identified in many adult tissues. MSCs can regenerate through cell division or differentiate into adipocytes, osteoblasts and chondrocytes. As a result, MSCs have become an important source of cells in tissue engineering and regenerative medicine for bone tissue and cartilage. Several epigenetic factors are believed to play a role in MSCs differentiation. Among these, microRNA (miRNA) regulation is involved in the fine modulation of gene expression during osteogenic/chondrogenic differentiation. It has been reported that miRNAs are involved in bone homeostasis by modulating osteoblast gene expression. In addition, countless evidence has demonstrated that miRNAs dysregulation is involved in the development of osteoporosis and bone fractures. The deregulation of miRNAs expression has also been associated with several malignancies including bone cancer. In this context, bone-associated circulating miRNAs may be useful biomarkers for determining the predisposition, onset and development of osteoporosis, as well as in clinical applications to improve the diagnosis, follow-up and treatment of cancer and metastases. Overall, this review will provide an overview of how miRNAs activities participate in osteogenic/chondrogenic differentiation, while addressing the role of miRNA regulatory effects on target genes. Finally, the role of miRNAs in pathologies and therapies will be presented.

Cytokines and pregnancy: Potential regulation by histone deacetylases.

Cytokines are important regulators of pregnancy and parturition. Aberrant expression of proinflammatory cytokines during pregnancy contributes towards preterm labor, pre-eclampsia, and gestational diabetes mellitus. The regulation of cytokine expression in human cells is highly complex, involving interactions between environment, transcription factors, and feedback mechanisms. Recent developments in epigenetic research have made tremendous advancements in exploring histone modifications as a key epigenetic regulator of cytokine expression and the effect of their signaling molecules on various organ systems in the human body. Histone acetylation and subsequent deacetylation by histone deacetylases (HDACs) are major epigenetic regulators of protein expression in the human body. The expression of various proinflammatory cytokines, their role in normal and abnormal pregnancy, and their epigenetic regulation via HDACs will be discussed in this review.

METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial-mesenchymal transition of renal tubular cells in diabetic kidney disease.

Histone deacetylase 5 (HDAC5) belongs to class II HDAC subfamily and is reported to be increased in the kidneys of diabetic patients and animals. However, little is known about its function and the exact mechanism in diabetic kidney disease (DKD). Here, we found that HDAC5 was located in renal glomeruli and tubular cells, and significantly upregulated in diabetic mice and UUO mice, especially in renal tubular cells and interstitium. Knockdown of HDAC5 ameliorated high glucose-induced epithelial-mesenchymal transition (EMT) of HK2 cells, indicated in the increased E-cadherin and decreased α-SMA, via the downregulation of TGF-ß1. Furthermore, HDAC5 expression was regulated by PI3K/Akt signaling pathway and inhibition of PI3K/Akt pathway by LY294002 treatment or Akt phosphorylation mutation reduced HDAC5 and TGF-ß1 expression in vitro high glucose-cultured HK2 cells. Again, high glucose stimulation downregulated total m6A RNA methylation level of HK2 cells. Then, m6A demethylase inhibitor MA2 treatment decreased Akt phosphorylation, HDAC5, and TGF-ß1 expression in high glucose-cultured HK2 cells. In addition, m6A modification-associated methylase METTL3 and METTL14 were decreased by high glucose at the levels of mRNA and protein. METTL14 not METTL3 overexpression led to PI3K/Akt pathway inactivation in high glucose-treated HK2 cells by enhancing PTEN, followed by HDAC5 and TGF-ß1 expression downregulation. Finally, in vivo HDACs inhibitor TSA treatment alleviated extracellular matrix accumulation in kidneys of diabetic mice, accompanied with HDAC5, TGF-ß1, and α-SMA expression downregulation. These above data suggest that METTL14-regulated PI3K/Akt signaling pathway via PTEN affected HDAC5-mediated EMT of renal tubular cells in diabetic kidney disease.

Beneficial Effects of a Mixture of Algae and Extra Virgin Olive Oils on the Age-Induced Alterations of Rodent Skeletal Muscle: Role of HDAC-4.

Aging is associated with a progressive decline in skeletal muscle mass, strength and function (sarcopenia). We have investigated whether a mixture of algae oil (25%) and extra virgin olive oil (75%) could exert beneficial effects on sarcopenia. Young (3 months) and old (24 months) male Wistar rats were treated with vehicle or with the oil mixture (OM) (2.5 mL/kg) for 21 days. Aging decreased gastrocnemius weight, total protein, and myosin heavy chain mRNA. Treatment with the OM prevented these effects. Concomitantly, OM administration decreased the inflammatory state in muscle; it prevented the increase of pro-inflammatory interleukin-6 (IL-6) and the decrease in anti-inflammatory interleukin-10 (IL-10) in aged rats. The OM was not able to prevent aging-induced alterations in either the insulin-like growth factor I/protein kinase B (IGF-I/Akt) pathway or in the increased expression of atrogenes in the gastrocnemius. However, the OM prevented decreased autophagy activity (ratio protein 1A/1B-light chain 3 (LC3b) II/I) induced by aging and increased expression of factors related with muscle senescence such as histone deacetylase 4 (HDAC-4), myogenin, and IGF-I binding protein 5 (IGFBP-5). These data suggest that the beneficial effects of the OM on muscle can be secondary to its anti-inflammatory effect and to the normalization of HDAC-4 and myogenin levels, making this treatment an alternative therapeutic tool for sarcopenia.

AtHDA15 binds directly to COP1 positively regulating photomorphogenesis.

Reversible histone acetylation and deacetylation play crucial roles in modulating light-regulated gene expression during seedling development. However, it remains largely unknown how histone-modifying enzymes interpose within the molecular framework of light signaling network. In this study, we show that AtHDA15 positively regulates photomorphogenesis by directly binding to COP1, a master regulator in the repression of photomorphogenesis. hda15 T-DNA knock-out and RNAi lines exhibited light hyposensitivity with reduced HY5 and PIF3 protein levels leading to long hypocotyl phenotypes in the dark while its overexpression leads to increased HY5 concentrations and short hypocotyl phenotypes. In vivo and in vitro binding assays show that HDA15 directly interacts with COP1 inside the nucleus modulating COP1's repressive activities. As COP1 is established to act within the nucleus to regulate specific transcription factors associated with growth and development in skotomorphogenesis, the direct binding by HDA15 is predicted to abrogate activities of COP1 in the presence of light and modulate its repressive activities in the dark. Our results append the mounting evidence for the role of HDACs in post-translational regulation in addition to their well-known histone modifying functions.

Histone acetylation and the role of histone deacetylases in normal cyclic endometrium.

Histone acetylation is a critical epigenetic modification that changes chromatin architecture and regulates gene expression by opening or closing the chromatin structure. It plays an essential role in cell cycle progression and differentiation. The human endometrium goes through cycles of regeneration, proliferation, differentiation, and degradation each month; each phase requiring strict epigenetic regulation for the proper functioning of the endometrium. Aberrant histone acetylation and alterations in levels of two acetylation modulators - histone acetylases (HATs) and histone deacetylases (HDACs) - have been associated with endometrial pathologies such as endometrial cancer, implantation failures, and endometriosis. Thus, histone acetylation is likely to have an essential role in the regulation of endometrial remodelling throughout the menstrual cycle.

The Relationship between HDAC3 and Malignant Tumors: A Mini Review.

Histone deacetylases 3 (HDAC3) is a member of the histone deacetylases family. This family is associated with cellular physiological function, such as signal transduction, cell cycle, proliferation, apoptosis, and cardiac development. HDAC3 plays an important role in the progression of malignant tumors, especially in terms of proliferation, apoptosis, metastasis, angiogenesis, and anticancer drug resistance. This review discusses the basic elements of HDAC3 and the relationship between HDAC3 and malignant tumors.