HDAC10 deletion in Treg
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA544959 | ENA |
REPOSITORIES: ENA
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Project description:HDAC10–/– (B6N(Cg)-Hdac10tm1.1(KOMP)Mbp/J) and wild type (WT) CD4+CD25+ Treg were isolated and RNA procured. Single strand cDNA was generated, fragmented and labeled, and hybridized to Affymetrix GeneChip Mouse Gene 2.0 ST Arrays for microarray analysis.
2019-05-28 | GSE131794 | GEO
Project description:Treg cells and Treg-specific deletion of Blimp1
| PRJNA737436 | ENA
Project description:Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers. Targets and cancer-relevant functions of HDAC10 in leukemia cells are enigmatic. We used flow cytometry, confocal immunofluorescence, single-cell DNA electrophoresis, global RNA-sequencing, mass spectrometry-based proteomics, and quantitative measurement of protein acetylation sites to evaluate how HDAC10 controls cancer-relevant signaling pathways in leukemia cells. We demonstrate that a subset of human cultured and primary acute B-cell/T-cell leukemia and lymphoma cells require HDAC10 for their survival. In such cells, HDAC10 controls a MYC-dependent transcriptional induction of the DNA polymerase subunit POLD1. Consequently, inhibition of HDAC10 halts cells in the S and G2/M phases of the cell cycle and causes DNA breaks, and an accumulation of poly-ADP-ribose chains indicating unresolved DNA damage. These processes culminate in caspase-dependent apoptosis. We reveal that HDAC10 has a nuclear function controlling the MYC-POLD1 axis. HDAC10 maintains the processivity of DNA replication and genome integrity in leukemic cell subtypes. This mechanistically defined HDAC10ness could prospectively be exploited as treatment option.
2025-05-23 | GSE277944 | GEO
Project description:Cutaneous T-cell lymphomas (CTCL) are a group of rare hematological malignancies characterized by infiltration of malignant T-cells into the skin. Two main types of CTCL constitute of Mycosis Fungoides (MF), a more indolent form of the disease, and Sézary Syndrome (SS), the aggressive and leukemic variant with blood involvement. Sézary syndrome presents a significant clinical challenge due to its very aggressive nature, poor prognosis, and treatment resistance, and to date, the disease is known to be uncurable. Histone deacetylase inhibitors have gained attention in CTCL treatment with promising results, but they expose limited specificity and strong side effects. Recent genomic studies underscore the role of epigenetic modifiers in CTCL pathogenesis, prompting an investigation into HDAC10, a member of Class IIb HDACs, in SS. HDAC10 was investigated in different cancers, revealing its involvement in the cell cycle regulation, apoptosis, and autophagy, but its role in CTCL is unknown. In this study we aimed to determine the role of HDAC10 in Sezary Syndrome, focusing on its cellular localization, role in cell growth, and potential therapeutic target. We indicated that HDAC10 is overexpressed in SS patients and located mainly in the cytoplasm. Its overexpression leads to an inhibitory effect on apoptosis progression when exposed to the pro-apoptotic compound Camptothecin (CPT). Knockdown of HDAC10 resulted in reduced cell growth and induction of apoptosis and autophagy, highlighting its potential importance in CTCL pathogenesis. Whole transcriptome analysis indicated that HDAC10 is associated with crucial cancer-related pathways for example hematopoietic cell lineage, PI3K-Akt signaling pathway, pathways in cancer, Ras signaling pathway, MAPK signaling pathway or JAK-STAT signaling pathway, which are critical for the survival and proliferation of malignant T cells. Inhibition of HDAC10 with selective HDAC10i increased the sensitivity of Sézary cells to the pro-apoptotic compound camptothecin (CPT). Our findings demonstrate that HDAC10 plays a key role in the molecular background of Sézary syndrome, highlighting its importance in the cellular mechanisms of the disease
2025-02-07 | GSE273693 | GEO
Project description:Histone deacetylases (HDACs) comprise a family of 18 epigenetic modifiers. The biologically relevant functions of HDAC10 in leukemia cells are enigmatic. We demonstrate that human cultured and primary acute B-cell/T-cell leukemia and lymphoma cells require HDAC10 for their survival. In such cells, HDAC10 controls a MYC-dependent transcriptional induction of the DNA polymerase subunit POLD1. Consequently, pharmacological inhibition of HDAC10 causes DNA breaks and an accumulation of poly-ADP-ribose chains. These processes culminate in caspase-dependent apoptosis. These data reveal a nuclear function for HDAC10. HDAC10 controls the MYC-POLD1 axis to maintain the processivity of DNA replication and genome integrity. This mechanistically defined “HDAC10ness” could prospectively be exploited as treatment option for hematopoietic malignancies.
2025-07-14 | PXD058544 | Pride
Project description:Background: Periplocin, a bioactive compound extracted from Cortex periplocae, has long been employed in traditional medicine for its diverse therapeutic effects, particularly in alleviating inflammation and inhibiting cancer progression. However, despite its potential benefits, the underlying molecular mechanisms of periplocin, especially in the context of leukemia treatment, remain poorly elucidated, warranting further investigation to uncover its precise role and therapeutic targets. Methods: A comprehensive approach combining network pharmacology and transcriptomic analysis was utilized to identify HDAC10 as a critical downstream target of periplocin. Molecular docking and dynamic simulation studies were performed to elucidate the interaction between periplocin and HDAC10 at the molecular level. Additionally, functional assays, including apoptosis induction, cell cycle regulation, and pathway inhibition experiments, were conducted to validate the mechanistic role of HDAC10 and its relevance to periplocin's anti-leukemic effects. Results: Periplocin was identified as an effective inhibitor of HDAC10, binding specifically to its hydrophobic active pocket and suppressing its enzymatic activity. This inhibition disrupted downstream signaling, particularly the NF-κB pathway, leading to significant apoptosis and cell cycle arrest in leukemia cells. These results therapy, offering insights into its mechanism of action through HDAC10 targeting. Conclusion: In conclusion, periplocin, as a novel natural compound, exhibits significant anti-leukemia activity, highlighting its potential as a promising therapeutic candidate for leukemia treatment. The findings contribute to the growing interest in natural compounds as innovative solutions for addressing unmet clinical needs in hematological malignancies.
2025-07-16 | GSE289937 | GEO
Project description:Mef2d, Mef2c, HDAC1, HDAC2 and Dyrk1 are involved with Foxp3 Treg regulation. Conditional deletion of either gene in Foxp3 Treg (cre/loxP) was generated and RNA sequenced and analyzed via Novogene, Inc.
2019-10-29 | GSE139480 | GEO
Project description:The inflammasome initiates innate defense and inflammatory response by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It is comprised of an innate immune receptor/effector, pro-caspase-1 and a common adaptor molecule, ASC (apoptotic speck-containing protein with a CARD). Consistent with their pro-inflammatory function, inflammasome components including caspase-1, ASC and NLRP3, are known to exacerbate autoimmunity during experimental autoimmune encephalomyelitis (EAE) by enhancing IL-1 and IL-18 secretion in myeloid cells3-6. Here we show an unexpected function of a DNA-binding inflammasome effector, AIM2 (Absent in Melanoma 2)7-10, in restraining autoimmunity by performing EAE in both whole body and Treg-specific deletion of Aim2–/– mice. AIM2 is highly expressed by human and mouse Treg cells and it is essential to attenuate EAE. RNA-seq, biochemical and metabolic analyses revealed that AIM2 attenuates mTOR, Myc and immune-metabolic functions in both Treg cells isolated in vivo and Treg cells induced in vitro with TGF-. Importantly, we found AIM2 physically interacted with RACK1 in Treg cells to facility the PP2A/RACK1/Akt-mTOR signaling, which is identified as a central component downstream of AIM2 that controls Treg cell function and stability. While AIM2 is generally accepted as an inflammasome effector in myeloid cells, this report reveals a previously unappreciated T cell-intrinsic role of AIM2 in maintaining Treg cell function to restrain autoimmunity. This is achieved by diminishing Akt-mTOR signaling to regulate Treg stability under inflammation, and altering immune-metabolism in Treg cells.
2021-01-27 | PXD018638 | Pride
Project description:Whole transcriptome sequencing of Treg with and without Rcor1 deletion
| PRJNA564613 | ENA
Project description:Foxp3+ T-regulatory (Treg) cells have well established roles in maintaining immune homeostasis and tolerance, but the contributions of several large multiprotein complexes that regulate gene expression remain unexplored in Tregs. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex that consists of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1, Hdac2 and Lsd1 enzymes. We found Rcor1, Rcor2 and Lsd1 were physically associated with Foxp3, and that mice with conditional deletion of Rcor1 in Foxp3+ Treg cells had decreased proportions of Tregs in their peripheral lymphoid tissues, and increased Treg expression of IL-2 and IFN-g compared to WT cells. In vivo, compared with WT mice, mice with conditional deletion of Rcor1 in their Tregs had reduced suppression of homeostatic proliferation, inability to maintain long-term allograft survival despite costimulation blockade, and enhanced antitumor immunity in syngeneic models. Comparable findings were seen in WT mice treated with a CoREST inhibitor. Our data point to the potential for therapeutic modulation of Treg functions by pharmacologic targeting of enzymatic components of the CoREST complex, and contribute to an understanding of the biochemical and molecular mechanisms by which Foxp3 represses large gene sets and maintains the unique properties of this key immune cell type.
2019-09-10 | GSE137137 | GEO