Histone Deacetylase Gene Research Articles

Combination Strategy of Genetic Dereplication and Manipulation of Epigenetic Regulators Reveals a Novel Compound from Plant Endophytic Fungus.

The strategies of genetic dereplication and manipulation of epigenetic regulators to activate the cryptic gene clusters are effective to discover natural products with novel structure in filamentous fungi. In this study, a combination of genetic dereplication (deletion of pesthetic acid biosynthetic gene, PfptaA) and manipulation of epigenetic regulators (deletion of histone methyltransferase gene PfcclA and histone deacetylase gene PfhdaA) was developed in plant endophytic fungus Pestalotiopsis fici. The deletion of PfptaA with PfcclA and/or PfhdaA led to isolation of 1 novel compound, pestaloficiol X (1), as well as another 11 known compounds with obvious yield changes. The proposed biosynthesis pathway of pestaloficiol X was speculated using comparative analysis of homologous biosynthetic gene clusters. Moreover, phenotypic effects on the conidial development and response to oxidative stressors in the mutants were explored. Our results revealed that the new strain with deletion of PfcclA or PfhdaA in ΔPfptaA background host can neutralise the hyperformation of conidia in the PfptaA mutant, and that the ΔPfptaA ΔPfhdaA mutant was generally not sensitive to oxidative stressors as much as the ΔPfptaA ΔcclA mutant in comparison with the single mutant ΔPfptaA or the parental strains. This combinatorial approach can be applied to discover new natural products in filamentous fungi.

Histone deacetylase gene SlHDT1 regulates tomato fruit ripening by affecting carotenoid accumulation and ethylene biosynthesis

Fruit development and ripening is a complicated biological process, that is not only regulated by plant hormones and transcription factors, but also affected by epigenetic modifications. Histone deacetylation is an important way of epigenetic modification, and little information about it is available. In this study, an RNAi vector was constructed and transferred successfully into wild-type tomato for further research on the detailed functions of the histone deacetylation gene SlHDT1. The expression level of PSY1 was upregulated, and the transcription levels of LCY-B, LCY-E and CYC-B were downregulated, which was consistent with the increased accumulation of carotenoids. In addition, the expression levels of ethylene biosynthetic genes (ACS2, ACS4 and ACO1, ACO3), ripening-associated genes (RIN, E4, E8, PG, Pti4 and LOXB) and fruit cell wall metabolism genes (HEX, MAN, TBG4, XTH5 and XYL) were significantly upregulated further strengthening the results, including an increased ethylene content, advanced fruit ripening time and a shortened shelf life of tomato fruits. In addition, the increased total histone H3 acetylation level also provides evidence of a connection between epigenetic regulation by histone deacetylation and fruit development and ripening. Hence, SlHDT1 is a negative regulator and plays an essential role in regulating ethylene and carotenoid biosynthesis during fruit ripening through influences on the acetylation level.

Role of histone deacetylase inhibitors in androgenic callus induction of Oryza sativa sub indica, in sight into evolution and mode of action of histone deacetylase genes.

The potential of paddy breeding has reached its pinnacle, and hybrids have been the principal research outcome. Hence, our hypothesis was based on improvising the callus induction efficiency of recalcitrant Oryza sativa sub. indica hybrids by intervening into their cellular functions like cell division and histone regulation for the production of doubled haploids, a better output compared to hybrids. Insight into the mechanism of cell division is the foremost concern in altering the same and hence studies on evolution, expression and action of histone deacetylase and its 12 genes (9 HDA and 3 HD-tunin genes) were chosen in the hypothesis. Expression of HDA genes at three stages (anther dehiscence, 1st callusing and second callusing stages) with inhibitor (trichostatin-A) interventions indicated 1st callusing stage as the most important in influencing callus induction and also the genes HDA19, 6, 15 and 5 were the most important. TSA alone had a significant impact on the regulation of the genes HDT 702, HDA19, HDA9, and HDA6. Higher expression of HDA19 and HDA6 was involved in maximizing callus induction; HDA15 had an antagonistic expression compared to HDA19/6 and might be involved in chlorophyll regulation during regeneration. Results of evolutionary analysis on histone deacetylases indicated a long and single lineage of origin denoting its importance in the basic cellular functions. The tubulin deacetylation gene HDA5, which was exclusively found in dicotyledons, had a recent evolutionary history only from terrestrial plants, and also had significant conservation in its motifs and NLS region. By combating the recalcitrant nature of Indica cultivars, molecular editing on a combination of HDA genes will enhance the callus induction and regeneration efficiency of the next generation of doubled haploids, therby improving the total yield.

Histone deacetylase inhibition by suberoylanilide hydroxamic acid: a therapeutic approach to treat human uterine leiomyoma

To evaluate the effect of inhibition of histone deacetylases (HDACs) by suberoylanilide hydroxamic acid (SAHA) treatment of human uterine leiomyoma primary (HULP) cells invitro on cell proliferation, cell cycle, extracellular matrix (ECM) formation, and transforming growth factor β3 (TGF-β3) signaling. Prospective study comparing uterine leiomyoma (UL) vs. adjacent myometrium (MM) tissue and cells with or without SAHA treatment. Hospital and university laboratories. Women with UL without any hormone treatment. Myomectomy or hysterectomy surgery in women for leiomyoma disease. HDAC activity was assessed by enzyme-linked immunosorbent assay, and gene expression was assessed by quantitative real-time polymerase chain reaction. Effects of SAHA on HULP cells were analyzed by CellTiter(Promega, Madison, Wisconsin), Western blot, and quantitative real-time polymerase chain reaction. The expression of HDAC genes (HDAC1, fold change [FC] = 1.65; HDAC3, FC = 2.08; HDAC6, FC = 2.42) and activity (0.56 vs. 0.10 optical density [OD]/h/mg) was significantly increased in UL vs. MM tissue. SAHA decreased HDAC activity in HULP cells but not in MM cells. Cell viability significantly decreased in HULP cells (81.68% at 5 μM SAHA, 73.46% at 10 μM SAHA), but not in MM cells. Proliferating cell nuclear antigen expression was significantly inhibited in SAHA-treated HULP cells (5 μM SAHA, FC = 0.556; 10 μM SAHA, FC = 0.622). Cell cycle markers, including C-MYC (5 μM SAHA, FC = 0.828) and CCND1 (5 μM SAHA, FC = 0.583; 10 μM SAHA, FC = 0.482), were significantly down-regulated after SAHA treatment. SAHA significantly inhibited ECM protein expression, including FIBRONECTIN (5 μM SAHA, FC = 0.815; 10 μM SAHA, FC = 0.673) and COLLAGEN I (5 μM SAHA, FC = 0.599; 10 μM SAHA, FC = 0.635), in HULP cells. TGFβ3 and MMP9 gene expression was also significantly down-regulated by 10 μM SAHA (TGFβ3, FC = 0.596; MMP9, FC = 0.677). SAHA treatment inhibits cell proliferation, cell cycle, ECM formation, and TGF-β3 signaling in HULP cells, suggesting that histone deacetylation may be useful for treatment of UL.

Identification of the Histone Deacetylases Gene Family in Hemp Reveals Genes Regulating Cannabinoids Synthesis.

Histone deacetylases (HDACs) play crucial roles nearly in all aspects of plant biology, including stress responses, development and growth, and regulation of secondary metabolite biosynthesis. The molecular functions of HDACs have been explored in depth in Arabidopsis thaliana, while little research has been reported in the medicinal plant Cannabis sativa L. Here, we excavated 14 CsHDAC genes of C. sativa L that were divided into three relatively conserved subfamilies, including RPD3/HDA1 (10 genes), SIR2 (2 genes), and HD2 (2 genes). Genes associated with the biosynthesis of bioactive constituents were identified by combining the distribution of cannabinoids with the expression pattern of HDAC genes in various organs. Using qRT-PCR and transcription group analysis, we verified the expression of candidate genes in different tissues. We found that the histone inhibitor Trichostatin A (TSA) affected the expression of key genes in the cannabinoid metabolism pathway and the accumulation of synthetic precursors, which indirectly indicates that histone inhibitor may regulate the synthesis of active substances in C. sativa L.

N-acetyl l-aspartate and Triacetin modulate tumor suppressor MicroRNA and class I and II HDAC gene expression induce apoptosis in Glioblastoma cancer cells in vitro

Glioblastoma multiforme (GBM), grade IV glioma and is aggressive, malignant primary brain cancer. Altered expression and activity of epigenetic proteins such as histone deacetylases (HDACs) are involved in GBM metastasis. Also, acetates are important to brain metabolites that regulate cell proliferation and apoptosis. Here, we have examined the effect of the acetates on the cell-cycle. U87MG cancer cells treated with N-acetyl l-aspartate (NAA) and sodium acetate have exhibited G1 phase cell-cycle arrest whereas U87MG cells treated with Triacetin (TA), and potassium acetate has induced G2/M cell cycle arrest. We have observed inhibition of histone deacetylase (HDAC) mRNA levels in acetate treated U87MG cells. Interestingly, acetates-treated U87MG cells have shown a significant reduction in the mRNA level of class II HDACs than class I HDACs. Acetate treated cells have exhibited an enhanced expression of various microRNAs such as miR-15b, miR-92, miR-101, miR-155, miR-199, miR-200, miR-223, miR-16, and miR-17 that are involved in the inhibition of cancer cell proliferation, invasion, migration, and angiogenesis. Further, these acetate molecules regulate genes involved in mammalian target of rapamycin complex 2 (mTORC2) such as mammalian stress-activated protein kinase-interacting protein (mSIN1), protein observed with Rictor 2 (Protor 2), and protein kinase C α (PKCα). The present study reveals the possible involvement of the mTORC2 complex during acetate-mediated HDAC inhibition, as well as microRNA modulation. Furthermore, molecular modeling studies were employed to understand the binding mode of these acetate molecules to mTOR, Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), and HDAC-8 proteins. Thus in this study, we have identified the pivotal role of acetates in the modulation of mTOR complex, epigenetic genes and provide structural as well as functional insights that will help in future drug discovery against GBM cancer therapy.

Genetic screen for suppressors of increased silencing in rpd3 mutants in Saccharomyces cerevisiae identifies a potential role for H3K4 methylation.

Several studies have identified the paradoxical phenotype of increased heterochromatic gene silencing at specific loci that results from deletion or mutation of the histone deacetylase (HDAC) gene RPD3. To further understand this phenomenon, we conducted a genetic screen for suppressors of this extended silencing phenotype at the HMR locus in Saccharomyces cerevisiae. Most of the mutations that suppressed extended HMR silencing in rpd3 mutants without completely abolishing silencing were identified in the histone H3 lysine 4 methylation (H3K4me) pathway, specifically in SET1, BRE1, and BRE2. These second-site mutations retained normal HMR silencing, therefore, appear to be specific for the rpd3Δ extended silencing phenotype. As an initial assessment of the role of H3K4 methylation in extended silencing, we rule out some of the known mechanisms of Set1p/H3K4me mediated gene repression by HST1, HOS2, and HST3 encoded HDACs. Interestingly, we demonstrate that the RNA Polymerase III complex remains bound and active at the HMR-tDNA in rpd3 mutants despite silencing extending beyond the normal barrier. We discuss these results as they relate to the interplay among different chromatin-modifying enzyme functions and the importance of further study of this enigmatic phenomenon.

Molecular Cloning and Functional Verification of Histone Deacetylase Gene cobB in Vibrio alginolyticus

Molecular Cloning and Functional Verification of Histone Deacetylase Gene cobB in Vibrio alginolyticus

Histone deacetylase inhibitors improve MeJA-induced ginsenoside production in ginseng adventitious roots

Post-translational histone modifications such as histone acetylation play essential roles in plant growth, development, and stress responses by modulating gene expression. However, little is known about epigenetic regulation in plant secondary metabolism. To analyze the involvement of histone acetylation in elicitor-induced metabolite production, ginseng adventitious roots were treated with methyl jasmonate (MeJA) together with histone deacetylase (HDAC) inhibitors. Western blot results revealed that HDAC inhibitors cause hyperacetylation of histone H3, especially acetylation of histone H3 lysine 18, under MeJA treatment. In addition, the HDAC inhibitor-induced increase in the transcript levels of MeJA-induced ginsenoside biosynthetic genes resulted in enhancement of MeJA-induced ginsenoside production, indicating that HDAC activity serves as a negative factor in MeJA-induced transcriptional induction of ginsenoside biosynthesis pathways. In addition, we identified 25 HDAC genes from the ginseng genome, which suggested that MeJA-induced PgHDACs (PgHDA05, PgHDA10, PgHDA16, PgHDA17, PgHDA18, PgHDA19, and PgHDA20) might be key factors controlling MeJA-induced ginsenoside production in ginseng adventitious roots. This unique information regarding histone acetylation and ginsenoside production would be helpful in understanding epigenetic regulation in plant secondary metabolism.

Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia.

Cilia are evolutionarily highly conserved organelles with important functions in many organs. The extracellular component of the cilium protruding from the plasma membrane comprises an axoneme composed of microtubule doublets, arranged in a 9 + 0 conformation in primary cilia or 9 + 2 in motile cilia. These microtubules facilitate transport of intraflagellar cargoes along the axoneme. They also provide structural stability to the cilium, which may play an important role in sensory cilia, where signals are received from the movement of extracellular fluid. Post-translational modification of microtubules in cilia is a well-studied phenomenon, and acetylation on lysine 40 (K40) of alpha tubulin is prominent in cilia. It is believed that this modification contributes to the stabilization of cilia. Two classes of enzymes, histone acetyltransferases and histone deacetylases, mediate regulation of tubulin acetylation. Here we use a genetic approach, immunocytochemistry and behavioral tests to investigate the function of tubulin deacetylases in cilia in a zebrafish model. By mutating three histone deacetylase genes (Sirt2, Hdac6, and Hdac10), we identify an unforeseen role for Hdac6 and Sirt2 in cilia. As expected, mutation of these genes leads to increased acetylation of cytoplasmic tubulin, however, surprisingly it caused decreased tubulin acetylation in cilia in the developing eye, ear, brain and kidney. Cilia in the ear and eye showed elevated levels of mono-glycylated tubulin suggesting a compensatory mechanism. These changes did not affect the length or morphology of cilia, however, functional defects in balance was observed, suggesting that the level of tubulin acetylation may affect function of the cilium.

Differential Effects of Histone Deacetylases on the Expression of NKG2D Ligands and NK Cell-Mediated Anticancer Immunity in Lung Cancer Cells.

Histone acetylation is an epigenetic mechanism that regulates the expression of various genes, such as natural killer group 2, member D (NKG2D) ligands. These NKG2D ligands are the key molecules that activate immune cells expressing the NKG2D receptor. It has been observed that cancer cells overexpress histone deacetylases (HDACs) and show reduced acetylation of nuclear histones. Furthermore, HDAC inhibitors are known to upregulate the expression of NKG2D ligands. Humans have 18 known HDAC enzymes that are divided into four classes. At present, it is not clear which types of HDAC are involved in the expression of NKG2D ligands. We hypothesized that specific types of HDAC genes might be responsible for altering the expression of NKG2D ligands. In this study, we monitored the expression of NKG2D ligands and major histocompatibility complex (MHC) class I molecules in lung cancer cells which were treated with six selective HDAC inhibitors and specific small interfering RNAs (siRNAs). We observed that treatment with FK228, which is a selective HDAC1/2 inhibitor, also known as Romidepsin, induced NKG2D ligand expression at the transcriptional and proteomic levels in two different lung cancer cell lines. It also caused an increase in the susceptibility of NCI-H23 cells to NK cells. Silencing HDAC1 or HDAC2 using specific siRNAs increased NKG2D ligand expression. In conclusion, it appears that HDAC1 and HDAC2 might be the key molecules regulating the expression of NKG2D ligands. These results imply that specifically inhibiting HDAC1 and HDAC2 could induce the expression of NKG2D ligands and improve the NK cell-mediated anti-cancer immunity.

Allergoid–mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring

Allergoid-mannan conjugates are novel vaccines for allergen-specific immunotherapy being currently assayed in phase 2 clinical trials. Allergoid-mannan conjugates target dendritic cells (DCs) and generate functional forkhead box P3 (FOXP3)-positive Treg cells, but their capacity to reprogram monocyte differentiation remains unknown. We studied whether allergoid-mannan conjugates could reprogram monocyte differentiation into tolerogenic DCs and the underlying molecular mechanisms. Monocytes from nonatopic and allergic subjects were differentiated into DCs under conventional protocols in the absence or presence of allergoid-mannan conjugates. ELISA, real-time quantitative PCR, coculture, flow cytometry, and suppression assay were performed. Metabolic and epigenetic techniques were also used. Monocyte differentiation from nonatopic and allergic subjects into DCs in the presence of allergoid-mannan conjugates yields stable tolerogenic DCs. Lipopolysaccharide-stimulated mannan-tolDCs show a significantly lower cytokine production, lower TNF-α/IL-10 ratio, and higher expression of the tolerogenic molecules PDL1, IDO, SOCS1, SOCS3, and IL10; and they induce higher numbers of functional FOXP3+ Treg cells than conventional DC counterparts. Mannan-tolDCs shift glucose metabolism from Warburg effect and lactate production to mitochondrial oxidative phosphorylation. They also display epigenetic reprogramming involving specific histone marks within tolerogenic loci and lower expression levels of histone deacetylase genes. Mannan-tolDCs significantly increase the expression of the anti-inflammatory miRNA-146a/b and decrease proinflammatory miRNA-155. Allergoid-mannan conjugates reprogram monocyte differentiation into stable tolerogenic DCs via epigenetic and metabolic reprogramming. Our findings shed light on the novel mechanisms by which allergoid-mannan conjugates might contribute to allergen tolerance induction during allergen-specific immunotherapy.

Histone Epigenetic Signatures in Embryonic Limb Interdigital Cells Fated to Die.

During limb formation in vertebrates with free digits, the interdigital mesoderm is eliminated by a massive degeneration process that involves apoptosis and cell senescence. The degradation process is preceded by intense DNA damage in zones located close to methylated DNA, accompanied by the activation of the DNA repair response. In this study, we show that trimethylated histone 3 (H3K4me3, H3K9me3, and H3K27me3) overlaps with zones positive for 5mC in the nuclei of interdigital cells. This pattern contrasts with the widespread distribution of acetylated histones (H3K9ac and H4ac) and the histone variant H3.3 throughout the nucleoplasm. Consistent with the intense labeling of acetylated histones, the histone deacetylase genes Hdac1, Hdac2, Hdac3, and Hdac8, and at a more reduced level, Hdac10, are expressed in the interdigits. Furthermore, local treatments with the histone deacetylase inhibitor trichostatin A, which promotes an open chromatin state, induces massive cell death and transcriptional changes reminiscent of, but preceding, the physiological process of interdigit remodeling. Together, these findings suggest that the epigenetic profile of the interdigital mesoderm contributes to the sensitivity to DNA damage that precedes apoptosis during tissue regression.

Comparative Genome-Wide Analysis and Expression Profiling of Histone Acetyltransferases and Histone Deacetylases Involved in the Response to Drought in Wheat

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) contribute to plant growth, development, and stress responses. A number of HAT and HDAC genes have been identified in several plants. However, wheat HATs and HDACs have not been comprehensively characterized. In this study, 30 TaHAT genes and 53 TaHDAC genes were detected in the wheat genome. As described in other plants, TaHATs were classified into four subfamilies (i.e., GNAT, p300/CBP, MYST, and TAFII250) and TaHDACs were divided into three subfamilies (i.e., RPD3/HDA1, HD2, and SIR2). Phylogenetic and conserved domain analyses showed that TaHATs and TaHDACs are highly similar to those in Arabidopsis and rice; however, divergence and expansion from Arabidopsis and rice were also observed. We detected many stress-related cis-regulatory elements in the promoter regions of these genes (i.e., ABRE, STRE, MYB, etc.). Further, based on a comparative expression analyses of three varieties with different degrees of drought resistance under drought stress, we found that TaHAG2, TaHAG3, TaHAC2, TaHDA18, TaHDT1, and TaHDT2 are likely regulate drought stress in wheat.

Zinc oxide nanoparticles mediated substantial physiological and molecular changes in tomato.

There has long been debate about how nanoproducts meet agricultural requirements. This study aimed to investigate tomato responses to the long-time foliar application of zinc oxide nanoparticles (ZnO-NP; 0 and 3 mgl-1) or bulk type (BZnO). Both ZnO-NP and BZnO treatments, especially the nanoform, were significantly capable of improving growth, biomass, and yield. The ZnO-NP treatment upregulated the expression of the R2R3MYB transcription factor by 2.6 folds. The BZnO and ZnO-NP treatments transcriptionally up-regulated WRKY1 gene by 2.5 and 6.4 folds, respectively. The bHLH gene was also upregulated in response to BZnO (2.3-fold) or ZnO-NP (4.7-fold). Moreover, the ZnO-NP application made a contribution to upregulation in the EREB gene whereas the bulk compound did not make a significant change. Upregulation in the HsfA1a gene also resulted from the ZnO-NP (2.8-fold) or BZnO (1.6-fold) supplementation. The MKK2 and CAT genes displayed a similar upregulation trend in response to the supplements by an average of 3-folds. While the application of ZnO-NP slightly down-regulated the histone deacetylases (HDA3) gene by 1.9-fold, indicating epigenetic modification. The supplements, especially the nano-product, enhanced concentrations of K, Fe, and Zn in both leaves and fruits. The concentrations of Chla, Chlb, and carotenoids were increased in response to the BZnO or ZnO-NP treatments. Likewise, BZnO or ZnO-NP mediated an increase in activity of nitrate reductase and proline content in leaves. These treatments increased soluble phenols and phenylalanine ammonia-lyase activity. With a similar trend, the BZnO or ZnO-NP application improved the activities of catalase and peroxidase enzymes. The reinforcement in metaxylem and secondary tissues resulted from the applied supplements. This study provides comprehensive comparative evidence on how ZnO-NPs may remodel the chromatin ultrastructure and transcription program, and confer stress tolerance in crops. This study also underlines the necessity of providing integrated transcriptome and proteome data in future studies.

Comprehensive Analysis of the Histone Deacetylase Gene Family in Chinese Cabbage (Brassica rapa): From Evolution and Expression Pattern to Functional Analysis of BraHDA3

Histone deacetylases (HDACs) are known as erasers that remove acetyl groups from lysine residues in histones. Although plant HDACs play essential roles in physiological processes, including various stress responses, our knowledge concerning HDAC gene families and their evolutionary relationship remains limited. In Brassica rapa genome, we identified 20 HDAC genes, which are divided into three major groups: RPD3/HDA1, HD2, and SIR2 families. In addition, seven pairs of segmental duplicated paralogs and one pair of tandem duplicated paralogs were identified in the B. rapa HDAC (BraHDAC) family, indicating that segmental duplication is predominant for the expansion of the BraHDAC genes. The expression patterns of paralogous gene pairs suggest a divergence in the function of BraHDACs under various stress conditions. Furthermore, we suggested that BraHDA3 (homologous of Arabidopsis HDA14) encodes the functional HDAC enzyme, which can be inhibited by Class I/II HDAC inhibitor SAHA. As a first step toward understanding the epigenetic responses to environmental stresses in Chinese cabbage, our results provide a solid foundation for functional analysis of the BraHDAC family.

Methylxanthines and Neurodegenerative Diseases: An Update.

Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson’s disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.

Prevotella-rich enterotype may benefit gut health in finishing pigs fed diet with a high amylose-to-amylopectin ratio.

To investigate the influence of baseline enterotypes and dietary starch type on the concentration of short-chain fatty acids (SCFA), numbers of butyrate producing bacteria and the expression of genes related to intestinal barrier and inflammatory response in the colon of finishing pigs, a 60-d in vivo trial was conducted. A 2-wk pre-trial with 102 crossbred (Duroc × [Landrace × Yorkshire]) finishing barrows (90 d old) was conducted to screen enterotypes. Then, a total of 32 pigs (87.40 ± 2.76 kg) with high (HPBR, ≥ 14) and low (LPBR, ≤ 2) Prevotella-to-Bacteroides ratios (PBR) in equal measure were selected and randomly divided into 4 groups with 8 replicates per group and 1 pig per replicate. The trial was designed following a 2 (PBR) × 2 (amylose-to-amylopectin ratio, AMR) factorial arrangement. Pigs with different PBR were fed diets based on corn-soybean meal with high AMR (HAMR, 1.24) or low AMR (LAMR, 0.23), respectively. Results showed that neither PBR nor AMR influenced the growth performance of pigs. HPBR pigs fed HAMR diet had a higher number of colonic Clostridium cluster XIVa and higher gene expression of butyrate kinase compared to the LPBR pigs (P < 0.05). The HPBR pigs fed HAMR diets also had increased colonic concentrations of total SCFA and propionate compared to the LPBR pigs (P < 0.05). Comparing with other pigs, HPBR pigs fed HAMR diets showed a lower (P < 0.05) expression of histone deacetylases (HDAC) gene and higher (P < 0.05) expression of G protein-coupled receptor 43 gene (GPR 43) in the colonic mucosa. The interaction (P < 0.05) of HPBR and HAMR was also found to decrease the gene expression of interleukin (IL)-6, IL-12, IL-1β and tumor necrosis factor-α (TNF-α) in colonic mucosa. These findings show that HAMR diet increased the abundance and activity of butyrate-producing bacteria and the concentration and absorption of SCFA, which may be associated with the decreased gene expression of inflammatory cytokines in the colonic mucosa of pigs with Prevotella-rich enterotype. All these alterations are likely to have a positive effect on the intestinal health of finishing pigs.

Characteristic and evolution of HAT and HDAC genes in Gramineae genomes and their expression analysis under diverse stress in Oryza sativa.

Comprehensive characterization of Gramineae HATs and HDACs reveals their conservation and variation. The recent WGD/SD gene pairs in the CBP and RPD/HDA1 gene family may confer specific adaptive evolutionary changes. Expression of OsHAT and OsHDAC genes provides a new vision in different aspects of development and response to diverse stress. The histone acetylase (HAT) and histone deacetylase (HDAC) have been proven to be tightly linked to play a crucial role in plant growth, development and response to abiotic stress by regulating histone acetylation levels. However, the evolutionary dynamics and functional differentiation of HATs and HDACs in Gramineae remain largely unclear. In the present study, we identified 37 HAT genes and 110 HDAC genes in seven Gramineae genomes by a detailed analysis. Phylogenetic trees of these HAT and HDAC proteins were constructed to illustrate evolutionary relationship in Gramineae. Gene structure, protein property and protein motif composition illustrated the conservation and variation of HATs and HDACs in Gramineae. Gene duplication analysis suggested that recent whole genome duplication (WGD)/segmental duplication (SD) events contributed to the diversification of the CBP and RPD3/HDA1 gene family in Gramineae. Furthermore, promoter cis-element prediction indicated that OsHATs and OsHDACs were likely functional proteins and involved in various signaling pathways. Expression analysis by RNA-seq data showed that all OsHAT and OsHDAC genes were expressed in different tissues or development stages, revealing that they were ubiquitously expressed. In addition, we found that their expression patterns were altered in response to cold, drought, salt, light, abscisic acid (ABA), and indole-3-acetic acid (IAA) treatments. These findings provide the basis for further identification of candidate OsHAT and OsHDAC genes that may be utilized in regulating growth and development and improving crop tolerance to abiotic stress.

Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma

BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to...