The histone lysine demethylase Kdm6b is required for activity-dependent preconditioning of hippocampal neuronal survival
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE58398 | GEO | 2014/06/12
SECONDARY ACCESSION(S): PRJNA252502
REPOSITORIES: GEO
Similar Datasets
Project description:We profiled basal and bicuculline+4-AP inducible mRNA expression in cultured mouse hippocampal neurons with or without viral shRNA mediated knockdown of Kdm6b We harvested mRNA from neurons under four conditions (pLKO vector/treatment control, pLKO vector/3hr bicuculline+4AP, Kdm6b knockdown/treatment control,Kdm6b knockdown/3hr bicuculline+4AP). Libraries were generated and used for RNA sequencing.
2014-06-12 | E-GEOD-58398 | biostudies-arrayexpress
Project description:Enzymes that regulate histone lysine methylation play important roles in neuronal differentiation, but little is known about their contributions to activity-regulated gene transcription in differentiated neurons. We characterized activity-regulated expression of lysine demethylases and lysine methyltransferases in the hippocampus of adult male mice following pilocarpine-induced seizure. Pilocarpine drove a 20-fold increase in mRNA encoding the histone H3 lysine 27-specific demethylase Kdm6b selectively in granule neurons of the dentate gyrus, and this induction was recapitulated in cultured hippocampal neurons by bicuculline and 4-aminopyridine (Bic + 4AP) stimulation of synaptic activity. Because activity-regulated gene expression is highly correlated with neuronal survival, we tested the requirement for Kdm6b expression in Bic + 4AP induced preconditioning of neuronal survival. Prior exposure to Bic + 4AP promoted neuronal survival in control neurons upon growth factor withdrawal; however, this effect was ablated when we knocked down Kdm6b expression. Loss of Kdm6b did not disrupt activity-induced expression of most genes, including that of a gene set previously established to promote neuronal survival in this assay. However, using bioinformatic analysis of RNA sequencing data, we discovered that Kdm6b knockdown neurons showed impaired inducibility of a discrete set of genes annotated for their function in inflammation. These data reveal a novel function for Kdm6b in activity-regulated neuronal survival, and they suggest that activity- and Kdm6b-dependent regulation of inflammatory gene pathways may serve as an adaptive pro-survival response to increased neuronal activity.
| S-EPMC4138546 | biostudies-literature
Project description:Mutations in the JMJD3 (KDM6B) chromatin regulator are causally associated with autism spectrum disorder and syndromic intellectual disability, but the neurodevelopmental roles of this histone 3 lysine 27 (H3K27) demethylase are poorly understood. Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) generate new granule neurons throughout life, and deficits in DG neurogenesis are associated with cognitive and behavioral problems. Here we show that Jmjd3 is required for the establishment of adult neurogenesis in the mouse DG. Conditional deletion of Jmjd3 in embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs. While early postnatal mice with Jmjd3-deletion have near normal numbers of DG NSCs, at later stages, Jmjd3-deleted NSCs fail to propagate normally. In addition to the loss of NSCs during postnatal development, neurogenesis from Jmjd3-deleted NSCs is impaired, corresponding to defective neurogenic gene expression. Without Jmjd3, NeuroD2 and Bcl11b(Ctip2) are not properly expressed and exhibit increased levels of H3K27me3, underscoring the role of Jmjd3 in the regulation of transcription for neuronal differentiation. Thus, these data indicate that Jmjd3 plays dual roles in postnatal DG neurogenesis, being critical for the establishment of the NSC pool as well as the differentiation of young DG granule neurons. More broadly, our results suggest a neurodevelopmental link between JMJD3 mutations and hippocampal dysfunction, providing new insights into how mutations in chromatin regulators may contribute to learning disorders.
2021-04-01 | GSE73706 | GEO
Project description:The transcriptional and epigenetic regulation of CD8+ T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs. Here, we demonstrate that the Lysine Demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8+ T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (either T cell-specific KO or knockdown utilizing shRNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8+ T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.
2021-02-25 | GSE161842 | GEO
Project description:Genetic mutations in pancreatic ductal adenocarcinoma (PDAC) with critical roles have been well examined. The recent discovery of alterations in genes encoding histone modifiers suggests their possible roles in the complexity of cancer development. We previously reported loss of heterozygosity of the KDM6B gene, which encodes a histone demethylase for trimethylated histone H3 lysine 27 (H3K27me3), a repressive chromatin mark, in PDAC cells. In this study, we demonstrated that loss of KDM6B enhanced aggressiveness of PDAC cells. KDM6B has been regarded as a tumor suppressor that mediates oncogenic KRAS-induced senescence. Consistently, KDM6B was highly expressed in pancreatic precancerous lesions (pancreatic intraepithelial neoplasms); then, the expression decreased as the malignant grade progressed. We found that knockdown of KDM6B in PDAC cells promoted tumor sphere formation and increased peritoneal dissemination and liver metastasis in vivo. Microarray and chromatin immunoprecipitation analysis implicated CEBPA for aggressiveness induced by KDM6B knockdown. CEBPA knockdown recapitulated the phenotypic change of PDAC cells after KDM6B knockdown, which was reversed by forced expression of C/EBPα. Moreover, similar protein expression patterns of KDM6B and C/EBPα in human PDAC emphasized their functional correlation. Notably, pharmacological inhibition of the H3K27 methylase EZH2 in PDAC cells inhibited tumor sphere formation along with the upregulation of CEBPA expression, and this effect was impaired in KDM6B knockdown cells, highlighting the role for KDM6B in the activation of CEBPA. Together, our results propose a significant role for the KDM6B-C/EBPα axis in the PDAC phenotype.
2014-06-30 | GSE28155 | GEO
Project description:Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA). Rodents treated with IH exhibit hypertension. Hypoxia-inducible factor (HIF)-1-dependent transcriptional activation of NADPH oxidases (Nox) and the resulting increase in reactive oxygen species (ROS) levels is a major molecular mechanism underlying IH/OSA-induced hypertension. Jumanji C (JmjC)-containing histone lysine demethylases (JmjC-KDMs) are coactivators of HIF-1-dependent transcriptional activation. In the present study, we tested the hypothesis that JmjC-KDMs are required for IH-evoked HIF-1 transcriptional activation of Nox4 and the ensuing hypertension. Studies were performed on pheochromocytoma (PC)12 cells and rats. IH increased KDM6B protein and enzyme activity in PC12 cells in an HIF-1-independent manner as evidenced by unaltered KDM6B activation by IH in HIF-1α shRNA-treated cells. Cells treated with IH showed increased HIF-1-dependent Nox4 transcription as indicated by increased HIF-1α binding to hypoxia-responsive element (HRE) sequence of the Nox4 gene promoter demonstrated by chromatin immunoprecipitation (ChiP) assay. Pharmacological blockade of KDM6B with GSKJ4, a specific KDM6 inhibitor, or genetic silencing of KDM6B with shRNA abolished IH-induced Nox4 transcriptional activation by blocking HIF-1α binding to the promoter of the Nox4 gene. Treating IH-exposed rats with GSKJ4 showed: 1) absence of KDM6B activation and HIF-1-dependent Nox4 transcription in the adrenal medullae, and 2) absence of elevated plasma catecholamines and hypertension. Collectively, these findings indicate that KDM6B functions as a coactivator of HIF-1-mediated Nox4 transactivation and demonstrates a hitherto uncharacterized role for KDMs in IH-induced hypertension by HIF-1.
| S-EPMC8887999 | biostudies-literature
Project description:The JmjC domain containing protein JMJD3/KDM6B catalyses H3K27me3 and H3K27me2 demethylation. JMJD3 appears to be highly regulated at the transcriptional level and is upregulated in response to diverse stimuli such as differentiation inducers and stress signals. Accordingly, JMJD3 has been linked to the regulation of different biological processes such as differentiation of embryonic stem cells, inflammatory responses in macrophages, and induction of cellular senescence via regulation of the INK4A-ARF locus. Here we show here that JMJD3 interacts with the tumour suppressor protein p53. We find that the interaction is dependent on the p53 tetramerization domain. Following DNA damage, JMJD3 is transcriptionally upregulated and by performing genome-wide mapping of JMJD3, we demonstrate that it binds genes involved in basic cellular processes, as well as genes regulating cell cycle, response to stress and apoptosis. Moreover, we find that JMJD3 binding sites show significant overlap with p53 bound promoters and enhancer elements. The binding of JMJD3 to p53 target sites is increased in response to DNA damage, and we demonstrate that the recruitment of JMJD3 to these sites is dependent on p53 expression. Therefore, we propose a model in which JMJD3 is recruited to p53 responsive elements via its interaction with p53 and speculate that JMJD3 could act as a fail-safe mechanism to remove low levels of H3K27me3 and H3K27me2 to allow for efficient acetylation of H3K27. Examination of JMJD3 and p53 genome-wide binding in untreated BJ cells or cells exposed to DNA damage (IR, 10 Gy)
2014-06-11 | E-GEOD-55912 | biostudies-arrayexpress
Project description:To investigate how histone demethylases KDM4B and KDM6B may be involved in osteogenic commitment of mesenchymal stem cells (MSCs), we performed gene expression profiling and comparison on control, KDM4B- and KDM6B-knockdown MSCs at different stages of osteogenic differentiation. Human MSCs infected with scramble shRNAs, shRNAs against KDM4B or KDM6B are treated with BMP4/7 for 0, 4 and 24hrs. Total RNA were extracted from these 9 samples.
2012-07-31 | E-GEOD-36970 | biostudies-arrayexpress
Project description:In this study, we have investigated the effect of lysine-specific demethylase 6B (KDM6B) on gene expression in normal human germinal center (GC) B cells using a non-viral vector-based system. Gene expression was compared between KDM6B-transfected and control vector-transfected GC B cells from three patients. RNA from the MACS-sorted transfected GC B cells was amplified. 10ug of fragmented cRNA was hybridized to HG-U133 Plus 2.0 microarrays. Differentially expressed genes were identified using Affymetrix GCOS pairwise analysis.
2011-07-26 | E-GEOD-24044 | biostudies-arrayexpress
Project description:Medullary thymic epithelial cells (mTECs) play a central role in the establishment of T cell central immunological tolerance by promiscuously expressing tissue-restricted antigens (TRAs) and presenting them to developing T cells, leading to deletion of T cells responding to self-antigens. However, molecular mechanisms especially epigenetic regulation of mTEC homeostasis and TRA expression remain elusive. Here we show that the H3K27 demethylase Kdm6b is essential to maintain the postnatal thymic medulla by promoting mTEC survival and regulating the expression of TRA genes. Moreover, mice lacking Kdm6b developed pathological autoimmune disorders. Mechanically, Kdm6b exerted its function by reducing repressive H3K27 trimethylation (H3K27me3) at the promoters of anti-apoptotic gene Bcl2 and a set of Aire-dependent TRA genes. Thus, our findings reveal a dual role of Kdm6b in the regulation of mTEC-mediated T cell central tolerance.
| S-EPMC7493893 | biostudies-literature