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Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [ChIP-Seq]

ABSTRACT: To investigate the effect of SIRT2 inhibition on global epigenome profile, we inhibited SIRT2 using AGK2 and performed ChIP-seq analysis for enhnacers, transcription and repressor histone marks Our analysis reports global epigenome changes that is responsible for phenotype-reversal of gliomas as well as induction of terminal differentiation program.

ORGANISM(S): Mus musculus

PROVIDER: GSE234319 | GEO | 2023/06/15

REPOSITORIES: GEO

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Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [RNA-Seq]

Project description:To investigate the effect of SIRT2 inhibition on global transcriptomics profile, we inhibited Sirt2 using small molecules (AGK2) Our analysis reports phenotype-reversal of gliomas as well as induction of terminal differentiation program.

2023-06-15 | GSE234318 | GEO

Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-06-15 | GSE234320 | GEO

Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide

Project description:Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide

| PRJNA980742 | ENA

Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [RNA-Seq]

Project description:Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [RNA-Seq]

| PRJNA980744 | ENA

Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [ChIP-Seq]

Project description:Sirtuin 2 inhibition selectively induces senescence in ATRX-deficient malignant gliomas by modulating chromatin landscapes genome-wide [ChIP-Seq]

| PRJNA980743 | ENA

Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.

Project description:BackgroundFunctional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped.MethodsWe utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s).ResultsCMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. SIRT2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroepithelial progenitor cells (mNPCs), impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs), and increased expression of senescence markers in glioma models. Moreover, SIRT2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. These effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to SIRT2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon SIRT2 inhibition.ConclusionsOur findings indicate that SIRT2 inhibition selectively targets ATRX-deficient gliomas for senescence through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.

| S-EPMC10769000 | biostudies-literature

The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription

Project description:Aberrant expression of IL-17A together with abated IL-2 production by effector CD4+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here we report that Sirtuin 2 (SIRT2), a member of the family of NAD+-dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while it promotes their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K and the activation of the mTORC1/HIF-1α/RORγt pathway and the generation of Th17 cells differentiation. Additionally, SIRT2 is responsible for the deacetylation of c-Jun and histones on the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, binds directly to the Sirt2 promoter and promotes its transcription. AK-7, a SIRT2 inhibitor limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis and disease in the lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated their ability to differentiate into Th17 cells and promoted IL-2–producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential for the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new therapies for SLE.

2022-03-30 | GSE199496 | GEO

Sirtuin 2 Promotes HCMV Replication by Regulating Cell Cycle Progression

Project description:The host cell cycle is a major target for manipulation by viral pathogens, which often replicate in certain cell cycle stages. The prevalent pathogen human cytomegalovirus (HCMV), for instance, only replicates during G1 and therefore employs diverse mechanisms for regulating cell cycle progression. Here, we demonstrate that the human enzyme sirtuin 2 (SIRT2) is required for HCMV-mediated cell cycle dysregulation. By combining virology assays with mass pectrometry-based proteome, acetylome, and interactome analyses, we have defined a pro-virus function for SIRT2 in regulating the G1 to S phase transition.

2023-10-13 | PXD041171 | Pride

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.

Project description:Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

| S-EPMC3443254 | biostudies-literature

Clinical Neuropathology practice news 2-2014: ATRX, a new candidate biomarker in gliomas.

Project description:Genome-wide molecular approaches have substantially elucidated molecular alterations and pathways involved in the oncogenesis of brain tumors. In gliomas, several molecular biomarkers including IDH mutation, 1p/19q co-deletion, and MGMT promotor methylation status have been introduced into neuropathological practice. Recently, mutations of the ATRX gene have been found in various subtypes and grades of gliomas and were shown to refine the prognosis of malignant gliomas in combination with IDH and 1p/19q status. Mutations of ATRX are associated with loss of nuclear ATRX protein expression, detectable by a commercially available antibody, thus turning ATRX into a promising prognostic candidate biomarker in the routine neuropathological setting.

| S-EPMC3967248 | biostudies-literature

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