Myeloid-specific Hdac10 deletion protects against LPS-induced acute lung injury via P62 acetylation at lysine 165.

BACKGROUND: Aberrant activation of macrophages is associated with pathogenesis of acute lung injury (ALI). However, the potential pathogenesis has not been explored. OBJECTIVES: We aimed to identify whether histone deacetylase (HDAC) 10 is involved in lipopolysaccharide (LPS)-exposed ALI and reveal the underlying pathogenesis by which it promotes lung inflammation in LPS-exposed ALI via modifying P62 with deacetylation. METHODS: We constructed an ALI mice model stimulated with LPS to determine the positive effect of Hdac10 deficiency. Moreover, we cultured murine alveolar macrophage cell line (MH-S cells) and primary bone marrow-derived macrophages (BMDMs) to explore the pro-inflammatory activity and mechanism of HDAC10 after LPS challenge. RESULTS: HDAC10 expression was increased both in mice lung tissues and macrophage cell lines and promoted inflammatory cytokines production exposed to LPS. Hdac10 deficiency inhibited autophagy and inflammatory response after LPS stimulation. In vivo, Hdac10fl/fl-LysMCre mice considerably attenuated lung inflammation and inflammatory cytokines release exposed to LPS. Mechanistically, HDAC10 interacts with P62 and mediates P62 deacetylation at lysine 165 (K165), by which it promotes P62 expression and increases inflammatory cytokines production. Importantly, we identified that Salvianolic acid B (SAB), an HDAC10 inhibitor, reduces lung inflammatory response in LPS-stimulated ALI. CONCLUSION: These results uncover a previously unknown role for HDAC10 in regulating P62 deacetylation and aggravating lung inflammation in LPS-induced ALI, implicating that targeting HDAC10 is an effective therapy for LPS-exposed ALI.

Deficiency of histone deacetylases 3 in macrophage alleviates monosodium urate crystals-induced gouty inflammation in mice.

BACKGROUND: Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation. METHODS: Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein. RESULTS: Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1ß release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge. CONCLUSIONS: Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.

Deacetylase-dependent and -independent role of HDAC3 in cardiomyopathy.

Cardiomyopathy is a common disease of cardiac muscle that negatively affects cardiac function. HDAC3 commonly functions as corepressor by removing acetyl moieties from histone tails. However, a deacetylase-independent role of HDAC3 has also been described. Cardiac deletion of HDAC3 causes reduced cardiac contractility accompanied by lipid accumulation, but the molecular function of HDAC3 in cardiomyopathy remains unknown. We have used powerful genetic tools in Drosophila to investigate the enzymatic and nonenzymatic roles of HDAC3 in cardiomyopathy. Using the Drosophila heart model, we showed that cardiac-specific HDAC3 knockdown (KD) leads to prolonged systoles and reduced cardiac contractility. Immunohistochemistry revealed structural abnormalities characterized by myofiber disruption in HDAC3 KD hearts. Cardiac-specific HDAC3 KD showed increased levels of whole-body triglycerides and increased fibrosis. The introduction of deacetylase-dead HDAC3 mutant in HDAC3 KD background showed comparable results with wild-type HDAC3 in aspects of contractility and Pericardin deposition. However, deacetylase-dead HDAC3 mutants failed to improve triglyceride accumulation. Our data indicate that HDAC3 plays a deacetylase-independent role in maintaining cardiac contractility and preventing Pericardin deposition as well as a deacetylase-dependent role to maintain triglyceride homeostasis.

Metacyclogenesis defects and gene expression hallmarks of histone deacetylase 4-deficient Trypanosoma cruzi cells.

Trypanosoma cruzi-the causative agent of Chagas disease-like other kinetoplastids, relies mostly on post-transcriptional mechanisms for regulation of gene expression. However, trypanosomatids undergo drastic changes in nuclear architecture and chromatin structure along their complex life cycle which, combined with a remarkable set of reversible histone post-translational modifications, indicate that chromatin is also a target for control of gene expression and differentiation signals in these organisms. Chromatin-modifying enzymes have a direct impact on gene expression programs and DNA metabolism. In this work, we have investigated the function of T. cruzi histone deacetylase 4 (TcHDAC4). We show that, although TcHDAC4 is not essential for viability, metacyclic trypomastigote TcHDAC4 null mutants show a thin cell body and a round and less condensed nucleus located very close to the kinetoplast. Sixty-four acetylation sites were quantitatively evaluated, which revealed H2AT85ac, H4K10ac and H4K78ac as potential target sites of TcHDAC4. Gene expression analyses identified three chromosomes with overrepresented regions of differentially expressed genes in the TcHDAC4 knockout mutant compared with the wild type, showing clusters of either up or downregulated genes. The adjacent chromosomal location of some of these genes indicates that TcHDAC4 participates in gene expression regulation during T. cruzi differentiation.

HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness.

Hepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCC CSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinase-resistant HCC. SIGNIFICANCE: This study finds that HDAC11 suppresses LKB1 expression in HCC to promote cancer stemness, progression, and sorafenib resistance, suggesting the potential of targeting HDAC11 to treat HCC and overcome kinase inhibitor resistance.

HDAC5 inhibition reduces angiotensin II-induced vascular contraction, hypertrophy, and oxidative stress in a mouse model.

Non-specific histone deacetylase (HDAC) inhibition reduces high blood pressure in essential hypertensive animal models. However, the exact HDAC isoforms that play a critical role in controlling hypertension are not known. Here, we investigated the role of HDAC5 in vascular contraction, hypertrophy, and oxidative stress in the context of angiotensin II (Ang II)-induced hypertension. Genetic deletion of HDAC5 and treatment with class IIa HDAC inhibitors (TMP269 and TMP195) prevented Ang II-induced increases in blood pressure and arterial wall thickness. Hdac5-knockout mice were also resistant to the thromboxane A2 agonist (U46619)-induced vascular contractile response. Furthermore, the expression of Rho-associated protein kinase (ROCK) 2 was downregulated in the aortas of Ang II-treated Hdac5-knockout mice. Knockdown of HDAC5, RhoA, or ROCK2 reduced collagen gel contraction, whereas silencing of ROCK1 increased it. VSMC hypertrophy reduced on knocking down HDAC5, ROCK1, and ROCK2. Here we showed that genetic deletion of HDAC5 and pharmacological inhibition of class IIa HDACs ameliorated Ang II-induced ROS generation. Moreover, ROCK1 and ROCK2, the downstream targets of HDAC5, influenced ROS generation. The relative protein levels of HDAC5, ROCK1, and ROCK2 were increased both in the cytoplasm and nuclear fraction in response to Ang II stimulation in vascular smooth muscle cells. Inhibition of HDAC5 expression or activity reduced vascular hypertrophy, vasoconstriction, and oxidative stress in the Ang II-induced hypertension model. These findings indicate that HDAC5 may serve as a potential target in the treatment of hypertension.

Hdac3 deletion in myeloid progenitor cells enhances bone healing in females and limits osteoclast fusion via Pmepa1.

Previous studies examining the role of the histone deacetylase Hdac3 within myeloid cells demonstrated that Hdac3 promotes M2 activation and tissue healing in inflammatory conditions. Since myeloid lineage cells are required for proper bone formation and regeneration, in this study we examined the functions of Hdac3 during bone healing. Conditional deletion of Hdac3 within myeloid progenitors accelerates healing of cortical bone defects. Moreover, reduced osteoclast numbers within the defect site are correlated with Hdac3 suppression. Ex vivo osteoclastogenesis assays further demonstrate that Hdac3 deficiency limits osteoclastogenesis, the number of nuclei per cell and bone resorption, suggesting a defect in cell fusion. High throughput RNA sequencing identified the transmembrane protein Pmepa1 as a differentially expressed gene within osteoclast progenitor cells. Knockdown of Pmepa1 partially restores defects in osteoclastogenesis induced by Hdac3 deficiency. These results show that Hdac3 is required for optimal bone healing and osteoclast fusion, potentially via its regulation of Pmepa1 expression.

Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis.

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.

Hdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells.

Cytotoxic T cells play a key role in adaptive immunity by killing infected or cancerous cells. While the transcriptional control of CD8 T cell differentiation and effector function following T cell activation has been extensively studied, little is known about epigenetic regulation of these processes. Here we show that the histone deacetylase HDAC3 inhibits CD8 T cell cytotoxicity early during activation and is required for persistence of activated CD8 T cells following resolution of an acute infection. Mechanistically, HDAC3 inhibits gene programs associated with cytotoxicity and effector differentiation of CD8 T cells including genes encoding essential cytotoxicity proteins and key transcription factors. These data identify HDAC3 as an epigenetic regulator of the CD8 T cell cytotoxicity program.

Histone deacetylase 10 knockout activates chaperone-mediated autophagy and accelerates the decomposition of its substrate.

Histone deacetylase (HDAC) 10 is a member of class IIb HDACs, but its deacetylation targets and functions are poorly characterized. Recent investigation has proposed that HDAC10 deacetylates heat shock cognate protein 70 kDa (HSC70) after interaction. HSC70 plays an important role in chaperone-mediated autophagy (CMA), binding CMA substrates and transporting them to lysosomes. However, it has not been clarified whether HDAC10 is involved in CMA. In this study, we established the HDAC10 knockout HeLa cell line and evaluated its CMA activity to determine whether HDAC10 participates in regulating CMA. In HDAC10 knockout cells, lysosome-associated protein type 2A (LAMP2A) protein level increased and LAMP2A-positive lysosomes accumulated around the nucleus. Moreover, GAPDH, which is a well-known CMA substrate, was delivered to LAMP2A-positive lysosomes and degraded in HDAC10 knockout cells more efficiently than in wild type HeLa cells. These results suggest that CMA is activated in HDAC10 knockout cells. Meanwhile, turnover assay using LC3 and p62, which are macroautophagy markers, indicated that autophagic flux was fully functioning in HDAC10 knockout cells as well as in wild type HeLa cells. In conclusion, HDAC10 participated in regulating CMA, and HDAC10 knockout activated CMA and accelerated degradation of a CMA substrate.

Loss of HDAC3 contributes to meiotic defects in aged oocytes.

Maternal age-related decline in oocyte quality is associated with meiotic defects, but the underlying mechanisms remain to be explored. Histone deacetylase 3 (HDAC3) has been shown to govern multiple cellular events via deacetylating diverse substrates. We previously found that HDAC3 could promote meiotic apparatus assembly in mouse oocytes. In the present study, we identified a substantial reduction in HDAC3 protein in oocytes from old mice. Importantly, overexpression of HDAC3 in old oocytes not only partially prevents spindle/chromosome disorganization, but also significantly lowers the incidence of aneuploidy. Meanwhile, we noticed the elevated acetylation level of α-tubulin in oocytes derived from old mice. By employing site-directed mutagenesis, we showed that acetylation-mimetic mutant tubulin-K40Q disrupts the kinetochore-microtubule attachments and results in the assembly failure of meiotic apparatus in mouse oocytes. Importantly, forced expression of tubulin-K40R (nonacetylatable-mimetic mutant) was capable of alleviating the defective phenotypes of oocytes from aged mice. To sum up, this study uncovers that loss of HDAC3 represents one potential mechanism mediating the effects of advanced maternal age on oocyte quality.

HDAC3 Deficiency Promotes Liver Cancer through a Defect in H3K9ac/H3K9me3 Transition.

DNA damage triggers diverse cancers, particularly hepatocellular carcinoma (HCC), but the intrinsic link between DNA damage and tumorigenesis remains unclear. Because of its role as an epigenetic and transcriptional regulator, histone deacetylase 3 (HDAC3) is essential for DNA damage control and is often aberrantly expressed in human HCC. In this study, we used individual class I HDAC member-deficient mice to demonstrate that K9 in histone H3 (H3K9), which is the critical site for the assembly of DNA damage response complexes, is exclusively targeted by HDAC3. Ablation of HDAC3 disrupted the deacetylation and consequent trimethylation of H3K9 (H3K9me3), the first step in double-strand break repair, and led to the accumulation of damaged DNA. Simultaneously, hyperacetylated H3K9 (H3K9ac) served as a transcriptional activator and enhanced multiple signaling pathways to promote tumorigenesis. Together, these results show that HDAC3 targets the H3K9ac/H3K9me3 transition to serve as a critical regulator that controls both DNA damage repair and the transcription of many tumor-related genes. Moreover, these findings provide novel insights into the link between DNA damage and transcriptional reprogramming in tumorigenesis. SIGNIFICANCE: These findings show that HDAC3 exclusively regulates H3K9ac in response to DNA damage, and loss of HDAC3 activity shifts the balance from DNA damage control to protumorigenic transcriptional activity.

Cutting Edge: HDAC3 Protects Double-Positive Thymocytes from P2X7 Receptor-Induced Cell Death.

Intricate life-versus-death decisions are programmed during T cell development, and the regulatory mechanisms that coordinate their activation and repression are still under investigation. In this study, HDAC3-deficient double-positive (DP) thymocytes exhibit a severe decrease in numbers. The thymic cortex is rich in ATP, which is released by macrophages that clear apoptotic DP thymocytes that fail to undergo positive selection. We demonstrate that HDAC3 is required to repress expression of the purinergic receptor P2X7 to prevent DP cell death. HDAC3-deficient DP thymocytes upregulate the P2X7 receptor, increasing sensitivity to ATP-induced cell death. P2rx7/HDAC3-double knockout mice show a partial rescue in DP cell number. HDAC3 directly binds to the P2rx7 enhancer, which is hyperacetylated in the absence of HDAC3. In addition, RORγt binds to the P2rx7 enhancer and promotes P2X7 receptor expression in the absence of HDAC3. Therefore, HDAC3 is a critical regulator of DP thymocyte survival and is required to suppress P2X7 receptor expression.

Loss of HDAC3 results in nonreceptive endometrium and female infertility.

Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus and causes chronic pelvic pain and infertility. However, the exact mechanisms of the pathogenesis of endometriosis-associated infertility are unknown. Epigenetic dysregulation has recently been implicated in infertility. Here, we report a reduction of histone deacetylase 3 (HDAC3) protein amounts in eutopic endometrium of infertile women with endometriosis compared to a control group. To investigate the effect of HDAC3 loss in the uterus, we generated mice with conditional ablation of Hdac3 in progesterone receptor (PGR)-positive cells (Pgrcre/+Hdac3f/f ; Hdac3d/d ). Loss of Hdac3 in the uterus of mice results in infertility due to implantation failure and decidualization defect. Expression microarray and ChIP-seq analyses identified COL1A1 and COL1A2 as direct targets of HDAC3 in both mice and humans. Reduction of HDAC3 abrogated decidualization in a primary culture of human endometrial stromal cells (hESCs) similar to that observed in infertile patients with endometriosis. Whereas attenuation of HDAC3 resulted in p300 recruitment to Col1a1 and Col1a2 genes in the uterus of mice as well as hESCs, inhibition of p300 permitted hESCs to undergo decidualization. Collectively, we found attenuation of HDAC3 and overexpression of collagen type I in the eutopic endometrium of infertile patients with endometriosis. HDAC3 loss caused a defect of decidualization through the aberrant transcriptional activation of Col1a1 and Col1a2 genes in mice and COL1A1 and COL1A2 genes in humans. Our results suggest that HDAC3 is critical for endometrial receptivity and decidualization.

NCOR1-a new player on the field of T cell development.

Nuclear receptor corepressor 1 (NCOR1) is a transcriptional corepressor that links chromatin-modifying enzymes with gene-specific transcription factors. Although identified more than 20 years ago as a corepressor of nuclear receptors, the role of NCOR1 in T cells remained only poorly understood. However, recent studies indicate that the survival of developing thymocytes is regulated by NCOR1, revealing an essential role for NCOR1 in the T cell lineage. In this review, we will briefly summarize basic facts about NCOR1 structure and functions. We will further summarize studies demonstrating an essential role for NCOR1 in controlling positive and negative selection of thymocytes during T cell development. Finally, we will discuss similarities and differences between the phenotypes of mice with a T cell-specific deletion of NCOR1 or histone deacetylase 3 (HDAC3), because HDAC3 is the predominant member of the HDAC family that interacts with NCOR1 corepressor complexes. With this review we aim to introduce NCOR1 as a new player in the team of transcriptional coregulators that control T cell development and thus the generation of the peripheral T cell pool.

HDAC9 promotes brain ischemic injury by provoking IκBα/NF-κB and MAPKs signaling pathways.

Ischemic stroke is an acute cerebrovascular disease due to poor blood flow to the brain. Nevertheless, there is still no effective therapy for it and the pathology contributing to ischemic stroke is not fully understood. Histone Deacetylase 9 (HDAC9) is a class IIa chromatin-modifying enzyme. HDAC9 gene region is a leading risk locus for large artery atherosclerotic stroke. However, the mechanisms linking HDAC9 to ischemic remain elusive. In the study, we attempted to explore HDAC9-associated inflammatory response using the wild type (WT) and HDAC9-knockout (KO) mice with brain ischemic injury. The results indicated that WT mice with ischemia brain exhibited higher expression levels of HDAC9. HDAC9 depletion resulted in a decreased infarct volume and an improved neurological function in mice after ischemic reperfusion (I/R) injury. I/R injury markedly enhanced GFAP and Iba-1 expressions in cortex and HDAC9 knockout significantly reversed this up-regulation. Loss of HDAC9 inhibited the release of inducible NO-synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), and IL-18 in cortex, hippocampus and hypothalamus of mice with I/R injury, which occurred at the transcription levels. Furthermore, the inhibitory actions of HDAC9 deficiency were associated with the down-regulation of phosphorylated-IκBα, phosphorylated-nuclear factor-kappa B (NF-κB), and p-mitogen-activated protein kinases (MAPKs), including phosphorylated-p38, phosphorylated-extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated-c-Jun N-terminal kinase (JNK). Importantly, the in vitro study indicated that HDAC9 inhibition-reduced inflammation and activation of IκBα/NF-κB were restored by promoting MAPKs activity in LPS-stimulated cells. Our findings suggest that HDAC9 inhibition showed neuroprotective effects on ischemic stroke by restraining inflammation, which might help develop new and effective strategies for the therapeutic interventions in ischemic stroke.

Deregulation of secondary metabolism in a histone deacetylase mutant of Penicillium chrysogenum.

The Pc21 g14570 gene of Penicillium chrysogenum encodes an ortholog of a class 2 histone deacetylase termed HdaA which may play a role in epigenetic regulation of secondary metabolism. Deletion of the hdaA gene induces a significant pleiotropic effect on the expression of a set of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS)-encoding genes. The deletion mutant exhibits a decreased conidial pigmentation that is related to a reduced expression of the PKS gene Pc21 g16000 (pks17) responsible for the production of the pigment precursor naphtha-γ-pyrone. Moreover, the hdaA deletion caused decreased levels of the yellow pigment chrysogine that is associated with the downregulation of the NRPS-encoding gene Pc21 g12630 and associated biosynthetic gene cluster. In contrast, transcriptional activation of the sorbicillinoids biosynthetic gene cluster occurred concomitantly with the overproduction of associated compounds . A new compound was detected in the deletion strain that was observed only under conditions of sorbicillinoids production, suggesting crosstalk between biosynthetic gene clusters. Our present results show that an epigenomic approach can be successfully applied for the activation of secondary metabolism in industrial strains of P. chrysogenum.

The Deletion of Hdac4 in Mouse Osteoblasts Influences Both Catabolic and Anabolic Effects in Bone.

Histone deacetylase 4 (Hdac4) is known to control chondrocyte hypertrophy and bone formation. We have previously shown that parathyroid hormone (PTH) regulates many aspects of Hdac4 function in osteoblastic cells in vitro; however, in vivo confirmation was previously precluded by preweaning lethality of the Hdac4-deficient mice. To analyze the function of Hdac4 in bone in mature animals, we generated mice with osteoblast lineage-specific knockout of Hdac4 (Hdac4ob-/- ) by crossing transgenic mice expressing Cre recombinase under the control of a 2.3-kb fragment of the Col1a1 promoter with mice bearing loxP-Hdac4. The Hdac4ob-/- mice survive to adulthood and developed a mild skeletal phenotype. At age 12 weeks, they had short, irregularly shaped and stiff tails due to smaller tail vertebrae, with almost no growth plates. The tibial growth plate zone was also thinned, and Mmp13 and Sost mRNAs were increased in the distal femurs of Hdac4ob-/- mice. Immunohistochemistry showed that sclerostin was elevated in Hdac4ob-/- mice, suggesting that Hdac4 inhibits its gene and protein expression. To determine the effect of PTH in these mice, hPTH (1-34) or saline were delivered for 14 days with subcutaneously implanted devices in 8-week-old female Hdac4ob-/- and wild-type (Hdac4fl/fl ) mice. Serum CTX, a marker of bone resorption, was increased in Hdac4ob-/- mice with or without PTH treatment. Tibial cortical bone volume/total volume (BV/TV), cortical thickness (Ct.Th), and relative cortical area (RCA) were decreased in Hdac4ob-/- mice, but PTH caused no further decrease in Hdac4ob-/- mice. Tibial trabecular BV/TV and thickness were not changed significantly in Hdac4ob-/- mice but decreased with PTH treatment. These results indicate that Hdac4 inhibits bone resorption and has anabolic effects via inhibiting Mmp13 and Sost/sclerostin expression. Hdac4 influences cortical bone mass and thickness and knockout of Hdac4 prevents the catabolic effect of PTH in cortical bone. © 2018 American Society for Bone and Mineral Research.

The combination of NAD+-dependent deacetylase gene deletion and the interruption of gluconeogenesis causes increased glucose metabolism in budding yeast.

Metabolic engineering focuses on rewriting the metabolism of cells to enhance native products or endow cells with the ability to produce new products. This engineering has the potential for wide-range application, including the production of fuels, chemicals, foods and pharmaceuticals. Glycolysis manages the levels of various secondary metabolites by controlling the supply of glycolytic metabolites. Metabolic reprogramming of glycolysis is expected to cause an increase in the secondary metabolites of interest. In this study, we constructed a budding yeast strain harboring the combination of triple sirtuin gene deletion (hst3∆ hst4∆ sir2∆) and interruption of gluconeogenesis by the deletion of the FBP1 gene encoding fructose-1,6-bisphosphatase (fbp1∆). hst3∆ hst4∆ sir2∆ fbp1∆ cells harbored active glycolysis with high glucose consumption and active ethanol productivity. Using capillary electrophoresis-time-of-flight mass spectrometry (CE-TOF/MS) analysis, hst3∆ hst4∆ sir2∆ fbp1∆ cells accumulated not only glycolytic metabolites but also secondary metabolites, including nucleotides that were synthesized throughout the pentose phosphate (PP) pathway, although various amino acids remained at low levels. Using the stable isotope labeling assay for metabolites, we confirmed that hst3∆ hst4∆ sir2∆ fbp1∆ cells directed the metabolic fluxes of glycolytic metabolites into the PP pathway. Thus, the deletion of three sirtuin genes (HST3, HST4 and SIR2) and the FBP1 gene can allow metabolic reprogramming to increase glycolytic metabolites and several secondary metabolites except for several amino acids.

Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b.

Multiple epigenetic mechanisms, including histone acetylation and nucleosome remodeling, are known to be involved in long-term memory formation. Enhancing histone acetylation by deleting histone deacetylases, like HDAC3, typically enhances long-term memory formation. In contrast, disrupting nucleosome remodeling by blocking the neuron-specific chromatin remodeling subunit BAF53b impairs long-term memory. Here, we show that deleting HDAC3 can ameliorate the impairments in both long-term memory and synaptic plasticity caused by BAF53b mutation. This suggests a dynamic interplay exists between histone acetylation/deacetylation and nucleosome remodeling mechanisms in the regulation of memory formation.