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MRNA profiles of JMJD3 overexpression NB4 cells

ABSTRACT: Next Generation Sequencing Facilitates Quantitative Analysis of NB4 cells transduced with control or JMJD3-expression vector. JMJD3, a stress-inducible H3K27 demethylase, plays a critical regulatory role in the initiation and progression of malignant hematopoiesis. However, how this histone modifier effects in a cell type-dependent manner remains unclear. Here, we show that in contrast to its oncogenic effect in preleukemia state and lymphoid malignancies, JMJD3 relieves the differentiation-arrest of certain subtypes (such as M2 and M3) of acute myeloid leukemia (AML) cells. RNA-sequencing and ChIP-PCR analyses revealed that JMJD3 exerts anti-AML effect by directly modulating H3K4 and H3K27 methylation levels to activate the expression of a number of key myelopoietic regulatory genes. Mechanistic exploration identified a physical and functional association of JMJD3 with C/EBPb that presides the regulatory network of JMJD3. Thus, the leukemia regulatory role of JMJD3 varies in a disease phase- and lineage-dependent manner, and acts as a potential oncorepressor in certain subsets of AML largely by coupling to C/EBPb-centered myelopoietic program.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116499 | GEO | 2018/07/03

REPOSITORIES: GEO

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JMJD3 facilitates C/EBPβ-centered transcriptional program to exert oncorepressor activity in AML

Project description:JMJD3, a stress-inducible H3K27 demethylase, plays a critical regulatory role in the initiation and progression of malignant hematopoiesis. However, how this histone modifier effects in a cell type-dependent manner remains unclear. Here, we show that in contrast to its oncogenic effect in preleukemia state and lymphoid malignancies, JMJD3 relieves the differentiation-arrest of certain subtypes (such as M2 and M3) of acute myeloid leukemia (AML) cells. RNA-sequencing and ChIP-PCR analyses revealed that JMJD3 exerts anti-AML effect by directly modulating H3K4 and H3K27 methylation levels to activate the expression of a number of key myelopoietic regulatory genes. Mechanistic exploration identified a physical and functional association of JMJD3 with C/EBPβ that presides the regulatory network of JMJD3. Thus, the leukemia regulatory role of JMJD3 varies in a disease phase- and lineage-dependent manner, and acts as a potential oncorepressor in certain subsets of AML largely by coupling to C/EBPβ-centered myelopoietic program. This SuperSeries is composed of the SubSeries listed below.

2018-06-12 | GSE101891 | GEO

Histone demethylase JMJD3 is a key epigenetic activator of FGF21 signaling-induced hepatic autophagy and lipolysis

Project description:Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we identify Jumonji-D3 (JMJD3/KDM6B) histone demethylase as a key epigenetic activator of hepatic autophagy. Upon fasting-induced fibroblast growth factor-21 (FGF21) signaling, JMJD3 epigenetically upregulated global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increased its nuclear localization and interaction with the nuclear receptor PPARto transcriptionally activate autophagy. Chronic administration of FGF21 in obese mice improved defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and KL were substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals

2020-05-26 | PXD015672 | Pride

The JMJD3-IRF4 axis regulates M2 macrophage polarization and host responses against helminth infection

Project description:Polarization of macrophages to M1 or M2 cells is important for mounting responses against bacterial and helminth infection respectively. Jumonji domain containing 3 (JMJD3), a histone 3 K27 demethylase, has been implicated in the activation of macrophages. Here we show that JMJD3 is essential for M2 macrophage polarization to helminth infection and chitin, though JMJD3 is dispensable for M1 responses. Furthermore, Jmjd3 is critical for proper bone marrow macrophage differentiation in a demethylase activity-dependent manner. Jmjd3 deficiency affected trimethylation of H3K27 in only a limited numbers of genes. Among them, we identified Irf4 as the target transcription factor critical for controlling M2 macrophage polarization. Collectively, these results show that JMJD3-mediated H3K27 demethylation is critical for regulating M2 macrophage development leading to anti-helminth host responses. This SuperSeries is composed of the SubSeries listed below.

2010-08-22 | GSE23306 | GEO

Genome wide H3K27ac status of endometrial stromal cells stimulated by cAMP, and cAMP under C/EBPb-knockdown

Project description:To know the role of C/EBPb in the changes of H3K27ac during desidualization, we compared the H3K27 profiles between cAMP-stimulation and cAMP-stimulation under C/EBPb-knockdown.

2021-02-17 | GSE148620 | GEO

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Project description:Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. We found that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification was associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cell (HSC) function and AML, such as HoxA cluster genes. In vivo, HMGN1 overexpression was linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperated with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieved the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.

2020-02-25 | PXD017054 | Pride

Genome wide trimethyl-H3K27 distibution in macrophages from wild-type and Jmjd3-/- macrophages.

Project description:Jmjd3 is trimethyl H3K27 specific demethylase required for M2 macrophage polarization. Genomic fragments obtained from wild-type and Jmjd3-/- mouse macrophages were immunoprecipitated with anti H3K27me3 Ab, and deep sequencing was performed. wild-type and Jmjd3-/- macrophages

2010-08-22 | E-GEOD-23297 | biostudies-arrayexpress

Epigenetic activation of neuronal gene expression by JMJD3 is required for postnatal and adult brain neurogenesis

Project description:The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here we show that JMJD3, a histone H3-lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis. 3 biological replicates of JMJD3 null (P9 UBC-Cre/ERT2;Jmjd3F/F) and 3 biological replicates of littermate controls were used to analyze the effect of JMJD3 deletion on gene expression.

2014-07-30 | E-GEOD-59888 | biostudies-arrayexpress

Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase

Project description:Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we identify Jumonji-D3 (JMJD3/KDM6B) histone demethylase as a key epigenetic activator of hepatic autophagy. Upon fasting-induced fibroblast growth factor-21 (FGF21) signaling, JMJD3 epigenetically upregulated global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increased its nuclear localization and interaction with the nuclear receptor PPARa to transcriptionally activate autophagy. Chronic administration of FGF21 in obese mice improved defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and bKL were substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.

2019-10-01 | GSE138157 | GEO

Histone demethylase JMJD3 is a key epigenetic activator of FGF21 signaling-induced hepatic autophagy and lipid degradation

Project description:Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we identify Jumonji-D3 (JMJD3/KDM6B) histone demethylase as a key epigenetic activator of hepatic autophagy. Upon fasting-induced fibroblast growth factor-21 (FGF21) signaling, JMJD3 epigenetically upregulated global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increased its nuclear localization and interaction with the nuclear receptor PPARa to transcriptionally activate autophagy. Chronic administration of FGF21 in obese mice improved defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and bKL were substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.

2019-09-18 | GSE137555 | GEO

Expression profiling by high throughput sequencing of THP-1 cells treated with AT or HA

Project description:Deregulation of transcription factor MYB contributes to the development of leukemia and other human cancers, making MYB an attractive target for drug development. We demonstrate that the natural sesquiterpene lactone (STL) 4,15-iso-atriplicolide tiglate (AT) is a novel potent inhibitor of MYB-dependent transcription. Further analysis revealed that C/EBPb, a transcription factor cooperating with MYB in myeloid cells, rather than MYB itself is inhibited by AT and related STLs. We show that these compounds induce apoptosis and differentiation in human acute myeloid leukemia (AML) cell lines and that ectopic expression of C/EBPbor of an activated version of MYB counteract these effects. Furthermore, gene expression profiling shows that AT as well as helenalin acetate, a compound previously shown to inhibit C/EBPb, affect the expression of a significant number of MYB-regulated genes although neither of these compounds targets MYB directly. Taken together these results suggest that C/EBPbp lays a key role in AML cells by cooperating with MYB and supporting its activity. Finally, we show that AT inhibits primary murine and human AML patient cells in colony formation assays significantly stronger than normal hematopoietic progenitor cells. In summary, our work identifies several related STLs as novel potential drugs targeting AML and highlights a novel role of C/EBPbas a pro-leukemogenic factor in AML cells. We hypothesize that MYB and C/EBPbact together in a transcriptional module to maintain an undifferentiated state of AML cells and that targeting of this module via MYB or C/EBPbmay have therapeutic potential against AML.

2021-04-22 | GSE128570 | GEO

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