Homo sapiens
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PROVIDER: PRJNA389771 | ENA |
REPOSITORIES: ENA
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Project description:Inhibitors of the histone methyltransferases EZH2/1 induce a potent antiviral state and suppress infection by diverse viral pathogens
| PRJNA389769 | ENA
Project description:Inhibitors of the histone methyltransferases EZH2/1 induce a potent antiviral state and suppress infection by diverse viral pathogens [RNA-Seq]
| PRJNA389770 | ENA
Project description:Epigenetic regulation is based upon a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets to treat a range of diseases including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach to control infection, persistence, and the resulting recurrent disease. The histone methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3 enriched chromatin domains. However, while EZH2/1 are implicated in repression of herpesviral gene expression, inhibitors of these enzymes suppressed HSV primary infection in vitro and in vivo. Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and anti-pathogen pathways as well as enhanced recruitment of immune cells to in vivo infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (hCMV, Adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through activation of cellular antiviral and immune responses.
2017-07-17 | GSE99840 | GEO
Project description:Epigenetic regulation is based upon a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets to treat a range of diseases including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach to control infection, persistence, and the resulting recurrent disease. The histone methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3 enriched chromatin domains. However, while EZH2/1 are implicated in repression of herpesviral gene expression, inhibitors of these enzymes suppressed HSV primary infection in vitro and in vivo. Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and anti-pathogen pathways as well as enhanced recruitment of immune cells to in vivo infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (hCMV, Adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through activation of cellular antiviral and immune responses.
2017-07-17 | GSE99839 | GEO
Project description:Here we report the discovery of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, their application across a large lymphoma cell panel and their efficacy in GCBDLBCL xenograft models. RNA-seq of KARPAS-422 cell line RNA, in duplicate, treated with DMSO as control, and EZH2 inhibitors CPI360, EPZ-6438 and GSK126. Eight samples in total.
2015-04-13 | E-GEOD-62056 | biostudies-arrayexpress
Project description:Canonically, Enhancer of Zeste Homolog 2 (EZH2) serves as the main catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediating H3K27me3 deposition and transcriptional repression. Here, we report that, in MLL1-rearranged acute leukemias, EZH2 has additional noncanonical functions by binding the oncoprotein cMyc at its non-PRC2 target sites where EZH2 uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Canonical (EZH2:PRC2) and noncanonical (EZH2-TAD:cMyc) activities of EZH2 both promote oncogenesis, thus explaining the slow and often ineffective antitumor effects by current catalytic inhibitors of EZH2. To suppress EZH2’s multifaceted activities in cancer, we employed the Proteolysis Targeting Chimera (PROTAC) technology and developed a small-molecule degrader, MS177, which achieved effective, on-target depletion of EZH2 and its interacting partners (i.e., both canonical EZH2:PRC2 and noncanonical EZH2:cMyc complexes). MS177-mediated onco-target degradation is cereblon- and proteasome-dependent. Compared to EZH2 enzymatic inhibitors, MS177 is fast-acting and much more potent in suppressing cancer growth. Overall, this study reveals noncanonical oncogenic functions of EZH2, and presents a highly effective PROTAC for targeting EZH2’s multifaceted tumorigenic actions and a novel and attractive therapeutic strategy for the treatment of EZH2-depdendent cancers.
2021-12-29 | GSE150745 | GEO
Project description:Canonically, Enhancer of Zeste Homolog 2 (EZH2) serves as the main catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediating H3K27me3 deposition and transcriptional repression. Here, we report that, in MLL1-rearranged acute leukemias, EZH2 has additional noncanonical functions by binding the oncoprotein cMyc at its non-PRC2 target sites where EZH2 uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Canonical (EZH2:PRC2) and noncanonical (EZH2-TAD:cMyc) activities of EZH2 both promote oncogenesis, thus explaining the slow and often ineffective antitumor effects by current catalytic inhibitors of EZH2. To suppress EZH2’s multifaceted activities in cancer, we employed the Proteolysis Targeting Chimera (PROTAC) technology and developed a small-molecule degrader, MS177, which achieved effective, on-target depletion of EZH2 and its interacting partners (i.e., both canonical EZH2:PRC2 and noncanonical EZH2:cMyc complexes). MS177-mediated onco-target degradation is cereblon- and proteasome-dependent. Compared to EZH2 enzymatic inhibitors, MS177 is fast-acting and much more potent in suppressing cancer growth. Overall, this study reveals noncanonical oncogenic functions of EZH2, and presents a highly effective PROTAC for targeting EZH2’s multifaceted tumorigenic actions and a novel and attractive therapeutic strategy for the treatment of EZH2-depdendent cancers.
2021-12-29 | GSE180447 | GEO
Project description:Canonically, Enhancer of Zeste Homolog 2 (EZH2) serves as the main catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediating H3K27me3 deposition and transcriptional repression. Here, we report that, in MLL1-rearranged acute leukemias, EZH2 has additional noncanonical functions by binding the oncoprotein cMyc at its non-PRC2 target sites where EZH2 uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Canonical (EZH2:PRC2) and noncanonical (EZH2-TAD:cMyc) activities of EZH2 both promote oncogenesis, thus explaining the slow and often ineffective antitumor effects by current catalytic inhibitors of EZH2. To suppress EZH2’s multifaceted activities in cancer, we employed the Proteolysis Targeting Chimera (PROTAC) technology and developed a small-molecule degrader, MS177, which achieved effective, on-target depletion of EZH2 and its interacting partners (i.e., both canonical EZH2:PRC2 and noncanonical EZH2:cMyc complexes). MS177-mediated onco-target degradation is cereblon- and proteasome-dependent. Compared to EZH2 enzymatic inhibitors, MS177 is fast-acting and much more potent in suppressing cancer growth. Overall, this study reveals noncanonical oncogenic functions of EZH2, and presents a highly effective PROTAC for targeting EZH2’s multifaceted tumorigenic actions and a novel and attractive therapeutic strategy for the treatment of EZH2-depdendent cancers.
2021-12-29 | GSE180446 | GEO
Project description:Canonically, Enhancer of Zeste Homolog 2 (EZH2) serves as the main catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediating H3K27me3 deposition and transcriptional repression. Here, we report that, in MLL1-rearranged acute leukemias, EZH2 has additional noncanonical functions by binding the oncoprotein cMyc at its non-PRC2 target sites where EZH2 uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Canonical (EZH2:PRC2) and noncanonical (EZH2-TAD:cMyc) activities of EZH2 both promote oncogenesis, thus explaining the slow and often ineffective antitumor effects by current catalytic inhibitors of EZH2. To suppress EZH2’s multifaceted activities in cancer, we employed the Proteolysis Targeting Chimera (PROTAC) technology and developed a small-molecule degrader, MS177, which achieved effective, on-target depletion of EZH2 and its interacting partners (i.e., both canonical EZH2:PRC2 and noncanonical EZH2:cMyc complexes). MS177-mediated onco-target degradation is cereblon- and proteasome-dependent. Compared to EZH2 enzymatic inhibitors, MS177 is fast-acting and much more potent in suppressing cancer growth. Overall, this study reveals noncanonical oncogenic functions of EZH2, and presents a highly effective PROTAC for targeting EZH2’s multifaceted tumorigenic actions and a novel and attractive therapeutic strategy for the treatment of EZH2-depdendent cancers.
2021-12-29 | GSE150823 | GEO
Project description:The closely related protozoan parasites Toxoplasma gondii and Neospora caninum display similar life cycles, subcellular ultrastructure, invasion mechanisms, metabolic pathways, and genome organization, but differ in their host range and disease pathogenesis. Type II (?) interferon has long been known to be the major mediator of innate and adaptive immunity to Toxoplasma infection, but genome-wide expression profiling of infected host cells indicates that Neospora is a potent activator of the type I (?/?) interferon pathways typically associated with antiviral responses. Infection of macrophages from mice with targeted deletions in various innate sensing genes demonstrates that host responses to Neospora are dependent on the toll-like receptor Tlr3 and the adapter protein Trif. Consistent with this observation, RNA from Neospora elicits type I interferon responses when targeted to the host endo-lysosomal system. While live Toxoplasma fails to induce type I interferon, heat-killed parasites do trigger this response, and co-infection studies reveal that T. gondii actively suppresses the production of type I interferon. These findings reveal that eukaryotic pathogens can be potent inducers of type I interferon and that some parasite species, like Toxoplasma gondii, have evolved mechanisms to suppress this response. In vitro cultures of bone marrow-derived macrophages from WT or IFNAR2-/- mice were infected with either Toxoplasma gondii (VEG strain) or Neospora caninum (Nc2 strain) for 17 hours. RNA was collected from biological replicates for expression profiling by microarray. Uninfected controls for both WT and IFNAR2-/- were used as a reference.
2013-03-29 | E-GEOD-45632 | biostudies-arrayexpress