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Analysis of the effect of cofactor knockdown on dexamethasone-induced gene expression in B-cell acute lymphoblastic leukemia

ABSTRACT: After identifying cofactors that affected the sensitivity of dex-induced cell death in B-ALL, we knocked down three cofactors, NCAO2, EHMT1, and EHMT2, using shRNAs in NALM6 cells After measuring the effect of cofactor knockdown on dex-sensitivity of these cells, we looked at differences in gene expression after exposure to dexamethasone.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118992 | GEO | 2018/08/24

REPOSITORIES: GEO

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Multi-omics analyses demonstrate a critical role for EHMT1 methyltransferase in transcriptionalrepression during oogenesis

Project description:EHMT1 (also known as GLP) is a multifunctional protein, best known for its role as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with EHMT2 (also known as G9A). Here, we investigated the role of EHMT1 in the oocyte in comparison to EHMT2 using oocyte-specific conditional knockout mouse models (Ehmt2 cKO, Ehmt1cKO, Ehmt1/2 cDKO), with ablation from the early phase of oocyte growth. Loss of EHMT1 in Ehmt1 cKO and Ehmt1/2 cDKO oocytes recapitulated meiotic defects observed in the Ehmt2 cKO; however, there was a significant impairment in oocyte maturation and developmental competence in Ehmt1 cKO and Ehmt1/2 cDKO oocytes beyond that observed in the Ehmt2cKO. Consequently, loss of EHMT1 in oogenesis results, upon fertilization, in mid-gestation embryonic lethality. To identify H3K9 methylation and other meaningful biological changes in each mutant to explore the molecular functions of EHMT1 and EHMT2, we performed immunofluorescence imaging, multi-omics sequencing, and mass spectrometry (MS)–based proteome analyses in cKO oocytes. Although H3K9me1 was depleted only upon loss of EHMT1, H3K9me2 was decreased, and H3K9me2-enriched domains were eliminated equally upon loss of EHMT1 or EHMT2. Furthermore, there were more significant changes in the transcriptome, DNA methylome, and proteome in Ehmt1/2 cDKO than Ehmt2 cKO oocytes, withtranscriptional derepression leading to increased protein abundance and local changes in genic DNA methylation in Ehmt1/2 cDKO oocytes. Together, our findings suggest that EHMT1 contributes to local transcriptional repression in the oocyte, partially independent of EHMT2, and is critical for oogenesis and oocyte developmental competence

2023-01-30 | PXD030265 | Pride

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome

Project description:Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/- adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/- mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/- mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/- mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.

2018-03-07 | GSE89010 | GEO

Histone methylation by the Kleefstra Syndrome protein EHMT1 mediates homeostatic synaptic scaling.

Project description:Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra syndrome-associated protein, EHMT1, plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vivo or in vivo. These findings suggest that changes in chromatin state through H3K9me2 governs a repressive program to achieve synaptic scaling. 12 samples (4 conditions in biological triplicate), 3 wt, 3 wt tetradotoxin treated, 3 k.d., 3 k.d. tetradotoxin treated

2016-06-30 | E-GEOD-68960 | biostudies-arrayexpress

Dexamethasone-resistant multiple myeloma cell line OPM1 treated with Dexamethasone and/or DAC

Project description:To identify genes responsible for the synergistic effect of DAC with Dex, we performed cDNA microarray analyses using cDNA prepared from Dex-resistant OPM1 cells treated with/without Dex, DAC or DAC+Dex.

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Promoter context-specific positive and negative transcriptional regulation of Glucocorticoid Receptor target genes by coregulator G9a

Project description:A549 lung cancer cells were not infected (NI), transfected by plasmids containing shG9a (sequence targeting G9a gene) or shNS (non-specific sequence). These cells were treated with dex to identify subsets of genes regulated by dex (hormone) and G9a (EHMT2) Cells (NI/shNS/shG9a) were treated with 100nM dex for 24h and total RNA was extracted to identify differentially expressed genes

2012-11-02 | E-GEOD-35962 | biostudies-arrayexpress

Promoter context-specific positive and negative transcriptional regulation of Glucocorticoid Receptor target genes by coregulator G9a

2012-11-02 | GSE35962 | GEO

Project description:EHMT1 and EHMT2 inhibition induce fetal hemoglobin expression

| PRJNA291181 | ENA

Role of EHMT1 in Alveolar Rhabdomyosarcoma

Project description:Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma, wherein the malignant tumors arise from the myoblast like cells due to the perturbations in growth and differentiation. Alveolar rhabdomyosarcoma (ARMS) is one of the two major histological subtypes which exhibits high metastatic potential and tumor recurrence culminating in poor prognosis. In the recent past, understanding the epigenetic modifications in these tumors with less genetic alterations has shed light on the process of tumor pathogenesis and development of potential epi-drugs for the effective treatment strategies. Epigenetic regulator, Euchromatin histone lysine methyltransferase 1 (EHMT1)/G9A-like protein (GLP) and its homolog Euchromatin histone lysine methyltransferase 1 (EHMT2)/G9A has been shown to promote proliferation and inhibit differentiation in the mouse myoblast cells, independently. Also, previous study from our lab reported the overexpression of EHMT2 and molecular mechanism associated with the oncogenic phenotype in ARMS. However, expression pattern and functional role of EHMT1 in ARMS is unknown. Herein, we investigated the role of EHMT1 in ARMS. Our preliminary data indicated the overexpression of EHMT1 and the associated oncogenic phenotypes in ARMS. Although EHMT1 has shown to be upregulated and correlated with the increased disease severity in several cancers including gastric, esophagus, squamous cell carcinoma, ovarian and breast cancer, the mechanism involved in the EHMT1 mediated tumorigenesis was unclear. Therefore, through our current study we aimed to understand the expression pattern and the mechanism through which EHMT1 regulated cancer phenotypes in ARMS, for this we performed whole transcriptomic analysis in ARMS cell lines upon EHMT1 knockdown for the first time. In addition, we also compared the expression levels of EHMT1 between Human skeletal muscle myoblasts (HSMM) and ARMS patient samples (obtained from St Jude cloud database).

2021-12-08 | GSE179049 | GEO

Expression data from pre-iPSCs with a control, histone methyltransferase or Cbx3 (HP1g) knockdown

Project description:Transition from a partially reprogrammed pre-iPSC state to iPSC state can be achieved by modulating levels of histone modifying enzymes or proteins that can bind to histone modifications We used microarrays to determine the gene expression profile of pre-iPSCs depleted for either 3 histone methyltransferases together or the HP1gamma protein pre-iPSCs were subjected to simultaneous siRNA mediated knockdown of Ehmt1, Ehmt2 and Setdb1- which is the 3XHMT sample that mediate H3k9me2/me3 or Cbx3( HP1gamma) or control siRNA to luciferase

2013-06-05 | E-GEOD-44084 | biostudies-arrayexpress

Promoter context-specific positive and negative transcriptional regulation of Glucocorticoid Receptor target genes by coregulator GLP.

Project description:A549 lung cancer cells were not infected (NI), transfected by plasmids containing shGLP (sequence targeting GLP gene) or shNS (non-specific sequence). These cells were treated with dex to identify subsets of genes regulated by dex (hormone) and GLP (EHMT1). NI and shNS data were submitted on the GSE35962.

2017-06-13 | GSE94646 | GEO

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