MiRNA expression of lymphoma cell lines with or without HDAC inhibitor treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE81190 | GEO | 2016/05/07
SECONDARY ACCESSION(S): PRJNA320856
REPOSITORIES: GEO
Similar Datasets
Project description:Long-term memory formation relies on synaptic plasticity, activity-dependent transcription and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes, and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional and epigenetic responses that are induced by CI-994, a class I HDAC inhibitor, combined with contextual fear conditioning (CFC) in mice. We show that CI-994-mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in contextual memory formation. Furthermore, using a combination of bulk and single cell RNA sequencing, we find that synaptic plasticity-promoting gene expression cascades are more strongly engaged in the hippocampus than in the striatum, but only when HDACi treatment co-occurred with CFC, and not by either treatment alone. Lastly, using ChIP-sequencing, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that may underlie improved memory performance. Together, our results indicate that systemic HDACi administration amplifies brain-region specific processes that are naturally induced by learning. These findings shed light onto the mode of action of HDACis as cognitive enhancers.
2022-05-16 | GSE185454 | GEO
Project description:Long-term memory formation relies on synaptic plasticity, activity-dependent transcription and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes, and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional and epigenetic responses that are induced by CI-994, a class I HDAC inhibitor, combined with contextual fear conditioning (CFC) in mice. We show that CI-994-mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in contextual memory formation. Furthermore, using a combination of bulk and single cell RNA sequencing, we find that synaptic plasticity-promoting gene expression cascades are more strongly engaged in the hippocampus than in the striatum, but only when HDACi treatment co-occurred with CFC, and not by either treatment alone. Lastly, using ChIP-sequencing, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that may underlie improved memory performance. Together, our results indicate that systemic HDACi administration amplifies brain-region specific processes that are naturally induced by learning. These findings shed light onto the mode of action of HDACis as cognitive enhancers.
2022-05-16 | GSE185453 | GEO
Project description:Long-term memory formation relies on synaptic plasticity, activity-dependent transcription and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes, and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional and epigenetic responses that are induced by CI-994, a class I HDAC inhibitor, combined with contextual fear conditioning (CFC) in mice. We show that CI-994-mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in contextual memory formation. Furthermore, using a combination of bulk and single cell RNA sequencing, we find that synaptic plasticity-promoting gene expression cascades are more strongly engaged in the hippocampus than in the striatum, but only when HDACi treatment co-occurred with CFC, and not by either treatment alone. Lastly, using ChIP-sequencing, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that may underlie improved memory performance. Together, our results indicate that systemic HDACi administration amplifies brain-region specific processes that are naturally induced by learning. These findings shed light onto the mode of action of HDACis as cognitive enhancers.
2022-05-16 | GSE185452 | GEO
Project description:HDAC inhibitors (HDACi) belong to a new group of chemotherapeutics that are increasingly used to treat B-cell-derived malignancies. Such malignancies regularly carry mutational signatures that conform to off-target induction of uracil by the AID/APOBEC family of cytidine deaminases, or downstream processing of uracil. . HDACi suppress thymidylate synthase increasing the cellular dUTP/dTTP ratio and leading to increased pressure on uracil repair machinery due to misincorporated uracil lesions. To investigate potential effect upon other enzymes involved in genomic uracil induction and processing, Jurkat (T-cell lymphoma) and SUDHL5 (B-cell lymphoma) cells were treated with pan-HDACi SAHA prior to SILAC based MS/MS investigation. HDACi treatment mediated significant differential expression of xx and xx proteins in Jurkat and SUDHL5, respectively, and had a substantial impact upon enzymes involved in in pyrimidine metabolism. Surprisingly, uracil N-glycosylase, UNG, was strongly downregulated by HDACi treatment. Further analysis in HEK and HeLa cells revealed that HDACis induce specific loss of the nuclear isoform UNG2 independent of transcription and cell-cycle alterations. More than 80% of UNG2 is degraded proteasomally after 24 hours treatment with SAHA, MS275, Valproate or Na-butyrate, indicating a universal ability of HDACis to mediate loss of UNG2. Targeted MS/MS analysis in HEK cells against a panel of proteins involved in DNA repair, translesion synthesis and nucleotide metabolism, revealed that UNG2 was the most pronounced differentially expressed among these after HDACi treatment. 48 hour treatment lead to a 30-40% increase in uracil lesions in the nuclear genome of HeLa and HEK cells and MS275 treatment in murine CH12F3 cell line mediated robust UNG2-loss accompanied by reduced class switch recombination. Furthermore, our analysis identified the PCNA-associated factor PAF15 among the downregulated proteins. PAF15 is overexpressed in many cancers and suppress TLS by inducing double monoubiquitinylation of PCNA and recruitment of the replicative polymerases. In summary, our findings demonstrate that HDAC inhibition affects the levels of proteins involved in DNA base excision repair, translesion synthesis and pyrimidine metabolism. These findings are important for a wide range of clinical applications of HDACi, such as in rheumatology, HIV-, and cancer treatment.
2020-04-14 | PXD008293 | Pride
Project description:Purpose: Gastric cancer remains one of the deadliest neoplasms worldwide, with a high need for new therapeutic options. Efficacies of targeted therapies are often limited owing to the inter- and intratumoral heterogeneity of gastric cancer. Thus, drugs with broader mechanisms of action rather than relying on the inhibition of a single specific oncogene are needed. Preclinical studies have identified histone deacetylases (HDAC) and their respective isoforms as potential therapeutic targets in gastric cancer. However, clinical efficacies are moderate and the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. Methods: In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured using flow cytometry. Proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA (RT-qPCR) and protein level (Western Blot). Results: Upon HDACi treatment, lipid peroxidation levels were found increased in all tested cell lines. Class-I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Alterations of POR and SLC7A11 levels upon treatment were also confirmed in primary human gastric cancer tissue cultures as relevant ex vivo model. Conclusion: We identify the induction of ferroptosis as a new mechanism of action of class-I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle besides other, less broadly usable targeted drugs.
2024-05-21 | PXD050328 | Pride
Project description:Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by Assay of Transposase-Accessible Chromatin (ATAC-seq). Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic vs. non-leukemic (host) CD4+ T cells in CTCL patients, vs. CD4+ T cells in healthy donors. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4+ T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.
2017-04-20 | GSE85853 | GEO
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162788 | GEO
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162786 | GEO
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162785 | GEO
Project description:Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain. The aim of this study was to determine whether these compounds could also affect neuropathic pain. Different class I HDACIs were delivered intrathecally into rat spinal cord in models of traumatic nerve injury and antiretroviral drug-induced peripheral neuropathy (stavudine, d4T). Mechanical and thermal hypersensitivity was attenuated by 40% to 50% as a result of HDACI treatment, but only if started before any insult. The drugs globally increased histone acetylation in the spinal cord, but appeared to have no measurable effects in relevant dorsal root ganglia in this treatment paradigm, suggesting that any potential mechanism should be sought in the central nervous system. Microarray analysis of dorsal cord RNA revealed the signature of the specific compound used (MS-275) and suggested that its main effect was mediated through HDAC1. Taken together, these data support a role for histone acetylation in the emergence of neuropathic pain. n = 4, HDACi treated vs. vehicle treated. Injured ipsilateral DRG after L5 spinal nerve transection. Spinal cord tissue was run in a separate Affymetrix experiment.
2013-10-01 | E-GEOD-51295 | biostudies-arrayexpress