ASO-mediated RNA Suppression through Targeted Epigenetic Reprogramming of the Hdac2 Gene
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ABSTRACT:
PROVIDER: PRJNA513334 | ENA |
REPOSITORIES: ENA
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Project description:We elicited ASO-mediated knockdown of mRNAs in the nervous system by targeting the memory-repressor gene Histone deacetylase 2 (Hdac2) in vitro and in vivo. We observed that an Hdac2-targeted ASO not only triggered a reduction in mRNA levels, but also a direct transcriptional suppression of the Hdac2 gene in neurons in vitro. In further in vivo studies, we observed that a single dose of the Hdac2-targeted ASO delivered by intracerebroventricular injection into the central nervous system (CNS) achieved steady-state diminution of Hdac2 mRNA levels that lasted more than 6 months in vivo. Knockdown of this factor resulted in memory enhancement. ASO administration also caused a prolonged alteration of steady-state levels of a set of known memory-associated mRNAs and triggered secondary changes in the epigenome at sites outside of the primary target gene.
2020-02-21 | GSE124726 | GEO
Project description:Hypoxia is a hallmark of cancer development. However, the molecular mechanisms by which hypoxia promotes tumor metastasis are not fully understood. In this study, we demonstrate that hypoxia promotes breast cancer metastasis through suppression of ΔNp63α-dependent in a HIF1α-independent manner. We show that hypoxia activates unfolded protein response (UPR) to elevate XBP1s, which in turn forms stable repressor protein complexes with HDAC2 and EZH2 in suppression of ΔNp63α. Notably, while H3K27ac is predominantly presented in the ΔNp63 promoter under normoxia, it is switched to H3K27me3 under hypoxia. We show that XBP1s binds to the ΔNp63 promoter to recruit HDAC2 and EZH2 in facilitating the H3K27ac-H3K27me3 switch. Knockdown or pharmacological inhibition of either HDAC2 or EZH2 leads to increased H3K27ac concomitant with reduced H3K27me3, which effectively restores ΔNp63α expression suppressed by hypoxia, resulting in inhibition of cell migration. Clinical analyses reveal that reduced p63 expression is correlated with the elevated expression of XBP1, HDAC2, or EZH2, and is associated with poor overall survival in human breast cancer patients. Together, these results indicate that hypoxia-activated XBP1s modulates the epigenetic program in suppression of ΔNp63α to promote breast cancer metastasis independent of HIF1α and provides a molecule basis for targeting the XBP1s/HDAC2/EZH2-ΔNp63α axis as a putative strategy in the treatment of breast cancer metastasis.
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Project description:Histone deacetylases (HDACs) are promising targets for cancer therapy, while their individual actions remain incompletely understood. Here, we identify a role for HDAC2 in regulation of
MDM2 acetylation at previously uncharacterized lysines. Upon inactivation of HDAC2, this acetylation creates a structural signal in the lysine-rich domain of MDM2 to prevent the recognition and degradation of its downstream substrate, MCL-1 Ubiquitin Ligase E3 (MULE). This mechanism further reveals a therapeutic connection between the MULE ubiquitin ligase function and tumor suppression. Specifically, we show that HDAC inhibitor treatment promotes the accumulation of MULE, which diminishes the t(X;18) translocation-associated synovial sarcomagenesis by directly targeting the fusion product SS18-SSX for degradation. These results
uncover a new HDAC2-dependent pathway that integrates reversible acetylation signaling to the anticancer ubiquitin response.
2020-03-22 | PXD012540 | JPOST Repository
Project description:To gain more insights into the functional significance of lnc-HLX-2-7, gene expression profiles were measured using D425 (sh-CTRL), D425 (sh-HLX) and intracranial D425 xenografts treated with ASO-CTRL and ASO-lnc-HLX 2-7 by RNA sequencing.
2023-11-01 | GSE188746 | GEO
Project description:Transcriptional profiling of mouse liver comparing control, scrambled-oligonucleotides (Cont)-treated mice with Perilipin 2-antisense oligonucleotides (Plin2-ASO)-treated mice. C57BL/6 mice on a high-fat diet were treated with oligonucleotides in vivo. The goal was to determine the effects of Plin2 down-regulation in the liver on global gene expression. Two-condition experiment, control oligonucleotides vs. Plin2-antisense oligonucleotides. Biological replicates: 4 control replicates, 4 Plin2-ASO replicates.
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Project description:Determine the effect and specificity of HDAC2 siRNA compared to SAHA inhibition of HDAC2 in hepatocellular carcinoma (HCC) Profile of treated cells compared to control Transcriptomic profiling
2014-10-02 | E-GEOD-52232 | biostudies-arrayexpress
Project description:Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.
2023-11-30 | GSE196843 | GEO
Project description:We have exploited organoid SILAC approaches that we have previously developed (A SILAC-Based Method for Quantitative Proteomic Analysis of Intestinal Organoids.- Gonneaud A, Jones C, Turgeon N, Lévesque D, Asselin C, Boudreau F, Boisvert FM. -Sci Rep. 2016 Nov 30;6:38195. doi: 10.1038/srep38195) to investigate proteomic changes after deletion of epigenetic eraser genes Hdac1 and Hdac2 in enteroids. Both HDAC1 and HDAC2 are epigenetic erasers that drive specific and redundant gene expression patterns, in part by removing acetyl groups on histones. Deletion of these Hdac in intestinal epithelial cell (IEC) in vivo alters intestinal homeostasis, dependent on the Hdac deleted and the level of expression of both. To determine the intrinsic specific IEC function of HDAC1 and HDAC2, we have performed transcriptomic and quantitative proteomic approaches on enteroids deficient in Hdac1 or Hdac2. We have defined changes in both mRNA and protein expression patterns affecting IEC differentiation. We have identified IEC Hdac1- and Hdac2-dependent common as well as specific pathways and biological processes. These findings uncover unrecognized similarities and differences between Hdac1 and Hdac2 in IEC.
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