Downregulation of HDAC9 by β-hydroxybutyrate suppresses vascular calcification in chronic kidney disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA775999 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16612775.fastq.gz | Fastqsanger.gz | |||
| SRR16612776.fastq.gz | Fastqsanger.gz | |||
| SRR16612777.fastq.gz | Fastqsanger.gz | |||
| SRR16612778.fastq.gz | Fastqsanger.gz | |||
| SRR16612779.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we report the protective effect of β-hydroxybutyrate (BHB) on vascular calcification in chronic kidney disease (CKD). To further investigate the mechanism underpinning the protective effect of BHB on vascular calcification, we performed high-throughput RNA-seq to identify the target gene of BHB. Our data demonstrate that BHB supplementation inhibits vascular calcification in CKD via targeting HDAC9.
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Project description:Vascular calcification contributes to the cardiovascular morbidity and mortality of chronic kidney disease (CKD), but there is no approved treatment for vascular calcification. In this study, we report the role of STING in vascular calcification. To further investigate the molecular mechanism by which STING participates in vascular calcification, we performed high-throughput RNA-seq to identify the target gene of STING.
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Project description:Muscle denervation due to injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and regeneration of neuromuscular synapses. Muscle activity inhibits neuromuscular synapse regeneration. The mechanism by which muscle activity regulates regeneration of synapses is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Here, we report that Dach2 and Hdac9 inhibit regeneration of neuromuscular synapses. Importantly, we identified Myog and Gdf5 as muscle-specific Dach2/Hdac9-regulated genes that stimulate neuromuscular regeneration in denervated muscle. Interestingly, Gdf5 also stimulates presynaptic differentiation and inhibits branching of regenerating neurons. Finally, we found that Dach2 and Hdac9 suppress miR206 expression, a microRNA involved in enhancing neuromuscular regeneration. RNAseq on innervated and 3 day denervated adult soleus muscle from wildtype mice is compared with that from 3 day denervated soleus muscle from Dach2/Hdac9 deleted mice to identify Dach2/Hdac9-regulated genes.
2015-10-29 | E-GEOD-58669 | biostudies-arrayexpress
Project description:Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced polyubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhanced VC. HDAC1 protein, but not mRNA, was reduced in cell and animal calcification models and in human calcified coronary artery. In the calcification-provoking condition, proteasomal degradation of HDAC1 preceded VC. The calcification-provoking condition induced MDM2 E3 ligase, which then resulted in HDAC1 K74 polyubiquitination. Overexpression of MDM2 enhanced VC, whereas loss of MDM2 blunted it. Decoy peptides spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevented VC in vivo and in vitro. These results demonstrate a previously unknown ubiquitination pathway and suggest MDM2-mediated HDAC1 polyubiquitination as a new therapeutic target in VC. Calcification was induced in rat aorta vascular smooth muscle cells with inorganic phosphate (Pi). Total RNA were extracted from the cells 3 and 6 days later. mRNA profile of the sample was compared with normal control.
2015-11-07 | E-GEOD-74755 | biostudies-arrayexpress
Project description:Patients with heterozygous missense mutations in the ACTA2 or MYH11 genes are known to exhibit thoracic aortic aneurysm (TAA) and a risk of early onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Recently an epigenetic complex containing the histone deacetylase HDAC9 and the long noncoding RNA, MALAT1 was implicated in pathologic vascular smooth muscle cell phenotypic changes in aneurysmal disease, however its involvement in stenotic disease has not been explored. Herein we implicate the HDAC9-MALAT1 complex in transcriptional silencing of contractile associated gene products, known to undergo downregulation in stenotic lesions. Furthermore, neointimal formation was inhibited in Hdac9 or Malat1 deficient mice with preservation of contractile protein expression. Pharmacologic targeting of the complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 reduced neointimal formation. In conclusion, we report the implication of the HDAC9-MALAT1 complex in stenotic disease and demonstrate that pharmacologic therapy based on epigenetic targets can ameliorate arterial obstruction in an experimental system.
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Project description:Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors.
2016-11-17 | GSE89954 | GEO
Project description:Vascular Calcification (VC) is a life threatening cardiovascular complication that accounts for high death rates particularly in association with diabetes, atherosclerosis and Chronic Kidney Disease (CKD. during VC, Vascular Smooth Muscle Cells (VSMCs) undergo reprogramming into osteoblast-like cells in response to calcium and phosphate mineral imbalance in CKD patients. This osteogenic switch is driven by the expression of several bone markers such as Runt- related transcription factor 2 (Runx2), Alkaline Phosphatase (ALP), Osteopontin (OPN), Matrix-Gla Protein (MGP), Osteocalcin (OCN), Type I Collagen (COL1), and Bone Sialo Proteins (BSPs). Recent studies showed that VSMCs secrete heterogeneous populations of Extracellular Vesicles (EVs)11 that are enriched under physiological conditions by calcification inhibitors such as Fetuin-A and MGP12,13,14. Interestingly, under pathological conditions, secreted EVs have a pro-calcifying profile and thereby act as nucleating foci for hydroxyapatite crystallization and propagation11,15. Electron Microscopy based studies revealed that EVs were embedded between collagen and elastin fibrils of arterial walls suggesting that calcification can be initiated through the EVs’ direct physical interaction with them13,16. We previously showed that a specific oligogalacturonic acid with a degree of polymerization of 8 (DP8) was able to inhibit vascular calcification. This inhibition was partly due to a decrease of osteogenic markers’s expression but also to the masking of a consensus sequence found in COL1 i.e. GFOGER sequence, thus preventing EVs from binding to COL1. Although the use of DP8 in-vivo seems to be compromised due to probable enzymatic digestion, these results suggested that the inhibition of VSMCs’ osteogenic switch and the prevention of EVs-COL1 interaction could represent new potential therapeutic targets for inhibiting VC17. Since we have already showed that the triple-helical GFOGER consensus sequence forms a preferential binding site for EVs17, we thereby chemically synthesized a GFOGER peptide in order to determine its ability to inhibit VC on VSMCs and on an aortic ring ex-vivo model. We also aim to decipher the mechanisms of inhibition by investigating the osteogenic markers’ expression as well as the protein content of secreted EVs in the presence of the GFOGER peptide.
2020-10-23 | PXD018169 | Pride
Project description:Background: Vascular calcification is a ubiquitous ageing pathology markedly accelerated in patients with metabolic disorders including diabetes and renal failure. Prelamin A is a biomarker of vascular ageing which accelerates vascular smooth muscle cell (VSMC) senescence and calcification. Using prelamin A as a model we explored the earliest events in VSMC ageing, focussing on the epigenetic landscape as an environmentally modifiable target. Methods: Adenoviral expression of prelamin A was used to induce VSMC ageing and epigenetic modifications were monitored using immunofluorescence and targeted PCR-arrays. Epigenetic findings were verified in vitro using drugs targeting epigenetic modifiers and in vivo using immunohistochemistry in human vessels from young, aged and calcified patients. Transcriptomics, ChIP-seq and antibody arrays were used to identify and verify gene targets impacted by changes in the epigenetic landscape and to monitor effects on inflammation, ageing indices and calcification. A novel mouse model of VSMC-specific inducible prelamin A expression was used to study epigenetic ageing in vivo and calcification was induced with vitamin D. Results: Prelamin A accumulation in VSMCs caused rapid global alterations in the repressive heterochromatin marks, H3K9me3 and H3K27me3 which coincided with downregulation of the epigenetic writers EZH2 and SUV39H1. These same epigenetic changes were recapitulated in primary human VSMCs induced to calcify in response to mineral dysregulation and in the calcified arteries of adults, and young children on dialysis. Global analysis of H3K9me3 and H3K27me3 marks in response to prelamin A expression showed deregulation of cross-talking NF-κB and HIPK2 stress response inflammatory pathways consistent with robust activation of a senescence associated secretory phenotype (SASP). Treatment of VSMCs with EZH2 and SUV39H1 inhibitors amplified the SASP and accelerated senescence and mineral deposition. Induction of prelamin A expression in VSMCs in mice induced rapid loss of heterochromatin which preceded DNA damage and senescence and coincided with early activation of SASP factors creating an environment permissive to calcification. Conclusions: Loss of heterochromatin is accelerated by metabolic disease and acts to promote VSMC inflammaging and a tissue microenvironment prone to calcification. Pre-senescent cells with an active SASP may be an early target for tackling vascular ageing pathologies. tackling vascular ageing pathologies.
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