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H3K27 methylation changes in Jurkat cells in response to TAL1-KD

ABSTRACT: T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and as such T-ALL treatments are uniformly applied across subtypes leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL whereby a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in dosage and activity of the histone 3 lysine 27 (H3K27) demethylase UTX. Specifically, we identify UTX as a co-activator of TAL1. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a potent oncogene essential for maintaining the leukemic phenotype of TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we designed a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that is highly effective against TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE72298 | GEO | 2016/02/01

SECONDARY ACCESSION(S): PRJNA293696

REPOSITORIES: GEO

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Gene expression in TAL1-driven T-cell ALL in response to TAL1-KD, UTX-KD, and GSKJ4 treatment

Project description:T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and as such T-ALL treatments are uniformly applied across subtypes leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL whereby a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in dosage and activity of the histone 3 lysine 27 (H3K27) demethylase UTX. Specifically, we identify UTX as a co-activator of TAL1. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a potent oncogene essential for maintaining the leukemic phenotype of TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we designed a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that is highly effective against TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.

2016-02-01 | GSE72299 | GEO

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency

Project description:This SuperSeries is composed of the following subset Series: GSE35775: The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression] GSE37821: The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [ChIP-Seq] Refer to individual Series

2012-05-29 | E-GEOD-37822 | biostudies-arrayexpress

Alternative mRNA splicing controls functions of the human H3K27 demethylase UTX/KDM6A

Project description:The UTX/KDM6A gene encodes the UTX histone H3K27 demethylase, which plays an important role in mammalian development and is frequently mutated in cancers and particularly, in urothelial cancers. Using BioID technique, we explored the interactome of different UTX isoforms.

2024-01-28 | PXD041254 | Pride

UTX Loss Alters Therapeutic Responses in KMT2A-rearranged Acute Myeloid Leukemia

Project description:Acute myeloid leukemias (AML) patients bearing chromosomal rearrangements of KMT2A or MLL gene (KMT2A -r) have poor overall survival. Recently, compounds targeting the KMT2A fusion protein complex, such as DOT1L and Menin inhibitors, have shown promising pre-clinical efficacy. Yet, molecular regulators of the anti-tumor activities of these agents remain poorly studied. UTX is a histone H3K27 demethylase with recurrent loss-of-function mutations in human cancers including leukemia. UTX-null leukemia shows greater resistance to chemotherapy agents. However, the impact of UTX on drug resistance of KMT2A -r AML has not been explored. Through a epigenetic compound screen, we identified a unique role of UTX in the regulation of DOT1L and Menin therapies in KMT2A-r AML. Loss of UTX confers resistance to DOT1L and Menin inhibition in an MLL target gene-independent manner. Mechanistically, We show that UTX is required for activation of myeloid differentiation programs induced by DOT1L inhibition. We also revealed BCL2A1 as a target of UTX. Depletion of UTX increased vulnerability to BCL2 inhibitor venetoclax in vitro and in vivo, and combinational treatment of venetoclax could overcome the therapeutic resistance to DOT1L inhibition caused by UTX loss. Our study provides new insights into the role of UTX in therapeutic responses in KMT2A-r AML.

2022-11-01 | GSE214275 | GEO

UTX Loss Alters Therapeutic Responses in KMT2A-rearranged Acute Myeloid Leukemia [ChIP-seq]

2022-11-01 | GSE214274 | GEO

UTX Loss Alters Therapeutic Responses in KMT2A-rearranged Acute Myeloid Leukemia [RNA-seq]

2022-11-01 | GSE214158 | GEO

RNA-Sequencing of primary myoblasts from mice with a satellite cell specific knockout of the histone demthylase UTX/KDM6A

Project description:The KDM6 histone demethylases (UTX/KDM6A and JMJD3/KDM6B) mediate removal of repressive histone H3K27me3 marks to establish transcriptionally permissive chromatin. Loss of UTX in female mice is embryonic lethal. Unexpectedly, male UTX-null mice escape embryonic lethality due to expression of UTY, a paralog lacking H3K27-demethylase activity. This suggests that UTX plays an enzyme-independent role in development, and challenges the need for active H3K27-demethylation in vivo. However, the requirement for active H3K27-demethylation in stem cell-mediated tissue regeneration remains untested. Using an inducible mouse knockout that ablates UTX in satellite cells, we show that active H3K27-demethylation is necessary for muscle regeneration. Indeed, loss of UTX in satellite cells blocks myofiber regeneration in both male and female mice. Furthermore, we demonstrate that UTX mediates muscle regeneration through its H3K27-demethylase activity using a chemical inhibitor, and a demethylase-dead UTX knock-in mouse. Mechanistically, dissection of the muscle regenerative process revealed that UTX is required for expression of the transcription factor Myogenin that drives differentiation of muscle progenitors. Thus, we have identified a critical role for the enzymatic activity of UTX in activating muscle-specific gene expression during myofiber regeneration, revealing for the first time that active H3K27-demethylation has a physiological role in vivo. Satellite cells were sorted based on Cre-dependent expression of TdT reporter gene. Sorted UTXmKO or UTX WT satellite cells were then induced to differentiate for 24 hrs. RNA was then isolated and subjected to RNA-Seq analysis.

2016-03-22 | E-GEOD-69968 | biostudies-arrayexpress

T cell UTX promotes Tfh-mediated clearance of persistent virus infection

Project description:Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, promotes the generation of T follicular helper (Tfh) cells, a CD4+ T cell subset essential for B cell antibody generation and clearance of chronic viral infections. Mice with T cell specific UTX deletion (UTX TKO mice) had fewer Tfh cells, showed defective germinal center formation, lacked virus-specific IgG production, and were unable to resolve chronic lymphocytic choriomeningitis virus infection. In UTX TKO T cells, decreased expression of IL-6R±, and other Tfh-related loci, was associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, have reduced UTX expression in immune cells and decreased Tfh frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection. Mice were infected with chronic LCMV and sorted for Tfh on day 21 pi (sorted for: CD4+CXCR5+CD62Llo T cell). ChIP-Seq and RNA-Seq on WT and Utx KO cells.

2015-09-01 | E-GEOD-64969 | biostudies-arrayexpress

RNA-Sequencing of primary myoblasts from mice with a satellite cell specific knockout of the histone demthylase UTX/KDM6A

2016-03-22 | GSE69968 | GEO

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression]

Project description:Pluripotency can be induced in somatic cells by ectopic expression of defined transcription factors, however the identity of epigenetic regulators driving the progression of cellular reprogramming requires further investigation. Here we uncover a non-redundant role for the JmjC-domain-containing protein histone H3 methylated Lys 27 (H3K27) demethylase Utx, as a critical regulator for the induction, but not for the maintenance, of primed and naM-CM-/ve pluripotency in mice and in humans. Utx depletion results in aberrant H3K27me3 repressive chromatin demethylation dynamics, which subsequently hampers the reactivation of pluripotency promoting genes during reprogramming. Remarkably, Utx deficient primordial germ cells (PGCs) display a cell autonomous aberrant epigenetic reprogramming in vivo during their embryonic maturation, resulting in the lack of functional contribution to the germ-line lineage. Samples include UTX+/Y (WT) and UTX-/Y (KO) cells from mouse ES cells and mouse embryonic fibroblast (MEF) before and after DOX induction (initiating reprogramming by OSKM factors). One sample is OSKM-induced Nanog-/- fibroblasts.

2012-05-29 | E-GEOD-35775 | biostudies-arrayexpress

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