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H3K27me3 demethylases maintain the transcriptional and epigenomic landscape of the intestinal epithelium [CHIP-seq]

ABSTRACT: To determine the contribution of H3K27me3 demethylases to intestinal homeostasis, an inducible mouse model was used to simultaneously ablate Kdm6a and Kdm6b expression from the intestinal epithelium. We then performed RNA-Seq gene expression analysis at two timepoints (7 days and 5 months) following induction of Kdm6a and Kdm6b ablation. Differential H3K27me3 regions were also identified using ChIP-Seq at one time point (7 days) following gene ablation.

ORGANISM(S): Mus musculus

PROVIDER: GSE200975 | GEO | 2022/12/31

REPOSITORIES: GEO

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H3K27me3 demethylases maintain the transcriptional and epigenomic landscape of the intestinal epithelium [RNA-seq]

Project description:To determine the contribution of H3K27me3 demethylases to intestinal homeostasis, an inducible mouse model was used to simultaneously ablate Kdm6a and Kdm6b expression from the intestinal epithelium. We then performed RNA-Seq gene expression analysis at two timepoints (7 days and 5 months) following induction of Kdm6a and Kdm6b ablation. Differential H3K27me3 regions were also identified using ChIP-Seq at one time point (7 days) following gene ablation.

2022-12-31 | GSE200974 | GEO

Characterizing the contrasting roles of JMJD3 and UTX histone demethylases in T cell acute lymphoblastic leukemia [shJMJD3_ChIP-seq]

2014-10-01 | E-GEOD-56692 | biostudies-arrayexpress

Impact of Jmjd3 and Utx histone demethylases on Histone H3 lysine 27 trimethylation (H3K27Me3) in mature CD4 SP thymocytes

Project description:While histone H3 lysine 27 trimethylation (H3K27Me3) is associated with gene silencing, whether H3K27Me3 demethylation affects transcription and cell differentiation in vivo has remained elusive. To investigate this, we conditionally inactivated the two H3K27Me3 demethylases, Jmjd3 and Utx, in non-dividing intrathymic CD4+ T cell precursors. We show that both enzymes redundantly promote H3K27Me3 removal at, and expression of, a specific subset of genes involved in terminal thymocyte differentiation, especially S1pr1, encoding a sphingosine-phosphate receptor required for thymocyte egress. Floxed alleles of the genes encoding Utx and Jmjd3 (Kdm6a and Kdm6b, respectively) were deleted in double positive (DP) thymocytes carrying a CD4 Cre transgene. Genome-wide H3K27Me3 ChipSeq was performed on (i) pre-selection (CD69lo) DP thymocytes from wild-type mice carrying an endogenous polyclonal TCR repertoire, (ii) mature (TCRhi CD24lo) CD4 SP thymocytes from wild type (Wt), Jmjd3KO, UtxKO and dKO mice carrying an endogenous polyclonal TCR repertoire and (iii) mature (Va2hi CD24lo) CD4 SP thymocytes from wild type and dKO mice carrying the OTII TCR transgene.

2015-09-02 | E-GEOD-70795 | biostudies-arrayexpress

Gene expression profiling in mature OT-II TCR transgenic CD4 SP thymocytes, either Jmjd3- and Utx-deficient or -sufficient.

Project description:The biological functions of histone demethylases Jmjd3 and Utx remain poorly understood. We assessed such functions in developing T cells, using conditional (CD4-Cre-mediated) gene disruption, by inactivating Kdm6a and Kdm6b, respectively encoding Utx and Jmjd3, in immature CD4+CD8+ thymocytes. We compared microarray gene expression in mature (Va2hi CD24lo) mutant and wild-type CD4+CD8- thymocytes carrying the OT-II TCR transgene. We show that Jmjd3 and Utx redundantly promote H3K27Me3 removal at, and expression of, a specific subset of genes involved in terminal thymocyte differentiation, especially S1pr1, encoding a sphingosine-phosphate receptor required for thymocyte egress. Mature (Va2hi CD24lo) CD4 thymocytes were sorted from freshly prepared single-cell suspensions OT-II TCR transgenic thymocytes deficient for Utx and Jmjd3 (dKO, CD4-Cre conditional deletion of floxed Kdm6a and Kdm6b alleles), and from Cre-negative controls (wild-type). Total RNA was extracted from sorted thymocytes using the RNeasy Plus Mini Kit (Qiagen) and processed for microarray analyses (Affymetrix Mouse Exon 1.0 ST array) at the NCI microarray facility, following the manufacturer’s recommendation. Data is generated from 3 replicates from each experiment.

2015-09-17 | E-GEOD-70363 | biostudies-arrayexpress

Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death (ChIP-seq)

Project description:Expression of the transcription factor brachyury (TBXT) is normally restricted to the embryo and its silencing is epigenetically regulated. TBXT promotes mesenchymal transition in a subset of common carcinomas, and in chordoma, a rare cancer showing notochordal differentiation, TBXT acts as a putative oncogene: we hypothesised that TBXT expression could be controlled through epigenetic inhibition to promote chordoma cell death. Screening of five human chordoma cell lines revealed that pharmacological inhibition of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (JMJD3) leads to cell death. This effect was phenocopied by the dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Inhibition of KDM6A/B using a novel compound, KDOBA67, led to a genome-wide increase in repressive H3K27me3 marks, with concomitant reduction in H3K27ac, H3K9ac and H3K4me3 active marks. We show that TBXT is a KDM6A/B target gene, and that changes in the chromatin at TBXT following KDOBA67 treatment were associated with a reduction in TBXT protein levels in all models tested, including primary patient-derived cultures. KDOBA67 downregulated also the expression of a network of transcription factors critical for chordoma survival, whereas upregulated pathways were dominated by ATF4-driven stress and pro-apoptotic responses in all models. Blocking the AFT4-stress response did not prevent the suppression of TBXT and induction of cell death, but viability was increased by ectopic overexpression of TBXT, therefore implicating TBXT as potential therapeutic target of H3K27 demethylases inhibitors. Our work highlights how knowledge of normal processes in fetal development can provide insight into tumourigenesis and identify novel therapeutic approaches.

2020-09-01 | GSE150600 | GEO

Characterizing the contrasting roles of JMJD3 and UTX histone demethylases in T cell acute lymphoblastic leukemia [shJMJD3_ChIP-seq]

2014-10-01 | GSE56692 | GEO

Characterizing the contrasting roles of JMJD3 and UTX histone demethylases in T cell acute lymphoblastic leukemia [short_hairpins_RNA-seq]

2014-10-01 | GSE56689 | GEO

KDM6 Inhibition induces DNA Damage Response (DDR) during ESC Differentiation but not during self-renewal.

Project description:The discovery of the first histone demethylase in 2004 (LSD1/KDM1) opened new avenues for the understanding of how histone methylation impacts cellular functions. A great number of histone demethylases have been identified since, which are potentially linked to gene regulation as well as to stem cell self-renewal and differentiation. KDM6A/UTY and KDM6B/JMJD3 are both H3K27me3/2-specific histone demethylases, which are known to play a central role in regulation of posterior development, by regulating HOX gene expression. So far nothing is known about the role of histone lysine demethylases (KDMs) during early hematopoiesis. We are studying the role of KDM6A and KDM6B on self-renewal, global gene expression and on local and global chromatin states in embryonic stem cells (ESCs) and during differentiation. In order to completely abrogate KDM6 demethylase activity in ESCs we employed a specific inhibitor (GSK-J4, Kruidenier et al. 2012). Treatment of ESCs with GSK-J4 had no effect on viability and proliferation . However, ESC differentiation in the presence of GSK-J4 was completely abrogated. In conclusion we show that ESC differentiation is completely blockend in the absence of any H3K27 demethylase activity. We used microarrays to detail the global gene expression program of genes which are differentially expressed during the early differentiation of ESC derived embryoid bodies (EBs) in the presence of GSK-J4 (KDM6 Inhibitor). ESCs (R1) have been cultured and differentiated in the presence of GSK-J4 a KDM6 specific inhibitor.

2016-03-11 | E-GEOD-49886 | biostudies-arrayexpress

Decoding changes in chromatin accessibility mediated by KDM6 histone demethylases [ATAC-seq]

Project description:To interrogate the function of KDM6A and KDM6B in regulating genome accessibility, we generated U937 cell lines having knockdown of either KDM6A, KDM6B or both using lentiviral shRNA. We then profiled chromatin accessibility changes using ATAC-seq data obtained from the 3 knockdown cell lines compared with the wild type cell line.

2023-01-29 | GSE223608 | GEO

Characterizing the contrasting roles of JMJD3 and UTX histone demethylases in T cell acute lymphoblastic leukemia [short_hairpins_RNA-seq]

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we abrogated the expression of JMJD3 (KDM6B) and UTX (KDM6A) H3K27me3 demethylases in human T-ALL lines and assayed for genome-wide expression changes using RNA sequencing. This piece of data was further integrated to ChIP-Sequencing analysis of H3K27me3 from the same treatment as well as H3K27me3 and JMJD3 genome-wide analysis from treatment of T-ALL lines with the GSKJ4 inhibitor. These results, coupled to genomic analysis of primary samples for the genomic status of the UTX gene in T-ALL, helped us to identify a hitherto unknown role of JMJD3as an oncogenice facilitator in leukemia whereas UTX seems to play a tumor suppressor role. Whole RNA was extracted from 1-5 million T-ALL (lines) cells or primary cells using the RNAeasy kit (Qiagen) according to the manufacturer’s protocol. Poly-A+ (magnetic oligodT-containing beads (Invitrogen)) or Ribominus RNA was used for library preparation. cDNA preparation and strand-specific library construction was performed using the dUTP method. Libraries were sequenced on the Illumina HiSeq 2000 using 50bp single-read method. Differential gene expression analysis was performed for each matched knockdown vs control pairs, separately in each biological or technical replicate in each of two cell lines (CUTLL1, CEM). Three types of comparisons were tested: (a) JMJD3 knockdown vs Renilla, (b) JMJD3 knockdown vs UTX knockdown, and (c) UTX knockdown vs Renilla. Analysis was performed using both DEGseq and Cufflinks packages leading to very similar conclusions.

2014-10-01 | E-GEOD-56689 | biostudies-arrayexpress

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