Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nodal signaling recruits the histone demethylase Jmjd3 to counteract polycomb-mediated repression at target genes.

ABSTRACT: Both intercellular signaling and epigenetic mechanisms regulate embryonic development, but it is unclear how they are integrated to establish and maintain lineage-specific gene expression programs. Here, we show that a key function of the developmentally essential Nodal-Smads2/3 (Smad2 and Smad3) signaling pathway is to recruit the histone demethylase Jmjd3 to target genes, thereby counteracting repression by Polycomb. Smads2/3 bound to Jmjd3 and recruited it to chromatin in a manner that was dependent on active Nodal signaling. Knockdown of Jmjd3 alone substantially reduced Nodal target gene expression, whereas in the absence of Polycomb, target loci were expressed independently of Nodal signaling. These data establish a role for Polycomb in imposing a dependency on Nodal signaling for the expression of target genes and reveal how developmental signaling integrates with epigenetic processes to control gene expression.

SUBMITTER: Dahle O

PROVIDER: S-EPMC6953396 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Nodal signaling recruits the histone demethylase Jmjd3 to counteract polycomb-mediated repression at target genes.

Dahle Øyvind Ø Kumar Amit A Kuehn Michael R MR

Science signaling 20100622 127

Both intercellular signaling and epigenetic mechanisms regulate embryonic development, but it is unclear how they are integrated to establish and maintain lineage-specific gene expression programs. Here, we show that a key function of the developmentally essential Nodal-Smads2/3 (Smad2 and Smad3) signaling pathway is to recruit the histone demethylase Jmjd3 to target genes, thereby counteracting repression by Polycomb. Smads2/3 bound to Jmjd3 and recruited it to chromatin in a manner that was de ...[more]

PMID: 20571128

Similar Datasets

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 report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates 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 increases its nuclear localization and interaction with the nuclear receptor PPAR? to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.

| S-EPMC7010817 | biostudies-literature

Palmitate-TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing.

Project description:Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4-/- ) or MyD88 (MyD88-/- ) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.

| S-EPMC8127612 | biostudies-literature

The localization of histone H3K27me3 demethylase Jmjd3 is dynamically regulated.

Project description:Jmjd3 is required for cellular differentiation and senescence, and inhibits the induction of pluripotent stem cells by demethylating histone 3 lysine 27 trimethylation (H3K27me3). Although recent studies reveal crucial biological roles for Jmjd3, it is unclear how its demethylase activity is controlled. Here, we show that nuclear localization of Jmjd3 is required for effective demethylation of H3K27me3. Our subcellular localization analysis of Jmjd3 shows that the N-terminal region of the protein is responsible for its nuclear placement, whereas the C-terminal region harboring the catalytic Jumonji C (JmjC) domain cannot situate into the nucleus. We identify two classical nuclear localization signals (cNLSs) in the N-terminal domain of Jmjd3. Forced nuclear emplacement of the catalytic domain of Jmjd3 by fusion with a heterologous cNLS significantly enhances its H3K27me3 demethylation activity. A dynamic nucleocytoplasmic shuttling of endogenous Jmjd3 occurs in mouse embryonic fibroblasts. Jmjd3 is localized both into the cytoplasm and the nucleus, and its nuclear export is dependent on Exportin-1, as treatment with leptomycin B triggers nuclear accumulation of Jmjd3. These results suggest that the subcellular localization of Jmjd3 is dynamically regulated and has pivotal roles for H3K27me3 status.

| S-EPMC4065181 | biostudies-literature

Histone demethylase JMJD3 is required for osteoblast differentiation in mice.

Project description:JMJD3 (KDM6B) is an H3K27me3 demethylases and emerges as an important player in developmental processes. Although some evidence indicated the involvement of JMJD3 in osteoblast differentiation in vitro, its role as a whole in osteoblast differentiation and bone formation in vivo remains unknown. Here we showed that homozygous deletion of Jmjd3 resulted in severe delay of osteoblast differentiation and bone ossification in mice. By biochemical and genetical methods, we demonstrated that JMJD3 mediated RUNX2 transcriptional activity and cooperated with RUNX2 to promote osteoblast differentiation and bone formation in vivo. These results strongly demonstrated that JMJD3 is required for osteoblast differentiation and bone formation in mice.

| S-EPMC4548232 | biostudies-other

Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression.

Project description:Jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, specifically catalyzes the demethylation of H3K27 (H3K27me3) and regulates gene expression. Sestrin2 (SESN2), a stress-inducible protein, protected against doxorubicin (DOX)-induced cardiomyopathy by regulating mitophagy and mitochondrial function. Here, the expression of JMJD3 was increased and that of SESN2 was decreased in both the heart samples from patients with dilated cardiomyopathy and chronic DOX-stimulation induced cardiomyopathy. Inhibition or knockdown of JMJD3 attenuated DOX-induced cardiomyocytes apoptosis, mitochondrial injury and cardiac dysfunction. However, JMJD3 overexpression aggravated DOX-induced cardiomyopathy, which were relieved by SESN2 overexpression. JMJD3 inhibited the transcription of SESN2 by reducing tri-methylation of H3K27 in the promoter region of SESN2. In conclusion, JMJD3 negatively regulated SESN2 via decreasing H3K27me3 enrichment in the promoter region of SESN2, subsequently inducing mitochondrial dysfunction and cardiomyocytes apoptosis. Targeting the JMJD3-SESN2 signaling axis may be a potential therapeutic strategy to protect against DOX-mediated cardiomyopathy.

| S-EPMC7552667 | biostudies-literature

Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms.

Project description:Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB-mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II-induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.

| S-EPMC8008365 | biostudies-literature

Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation.

Project description:Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3, but a role for JMJD3 in metabolic regulation has not been described. SIRT1 deacetylase maintains energy balance during fasting by directly activating both hepatic gluconeogenic and mitochondrial fatty acid β-oxidation genes, but the underlying epigenetic and gene-specific mechanisms remain unclear. In this study, JMJD3 was identified unexpectedly as a gene-specific transcriptional partner of SIRT1 and epigenetically activated mitochondrial β-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARα, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated β-oxidation-promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in β-oxidation, which contributed to hepatosteatosis as well as glucose and insulin intolerance. Remarkably, the lipid-lowering effects by JMJD3 or SIRT1 in diet-induced obese mice were mutually interdependent. JMJD3 histone demethylase may serve as an epigenetic drug target for obesity, hepatosteatosis, and type 2 diabetes that allows selective lowering of lipid levels without increasing glucose levels.

| S-EPMC6025975 | biostudies-literature

The histone demethylase Jmjd3 regulates zebrafish myeloid development by promoting spi1 expression.

Project description:The histone demethylase Jmjd3 plays a critical role in cell lineage specification and differentiation at various stages of development. However, its function during normal myeloid development remains poorly understood. Here, we carried out a systematic in vivo screen of epigenetic factors for their function in hematopoiesis and identified Jmjd3 as a new epigenetic factor that regulates myelopoiesis in zebrafish. We demonstrated that jmjd3 was essential for zebrafish primitive and definitive myelopoiesis, knockdown of jmjd3 suppressed the myeloid commitment and enhanced the erythroid commitment. Only overexpression of spi1 but not the other myeloid regulators rescued the myeloid development in jmjd3 morphants. Furthermore, preliminary mechanistic studies demonstrated that Jmjd3 could directly bind to the spi1 regulatory region to alleviate the repressive H3K27me3 modification and activate spi1 expression. Thus, our studies highlight that Jmjd3 is indispensable for early zebrafish myeloid development by promoting spi1 expression.

| S-EPMC5972518 | biostudies-other

AOF1 is a histone H3K4 demethylase possessing demethylase activity-independent repression function.

Project description:LSD1 (KDM1 under the new nomenclature) was the first identified lysine-specific histone demethylase belonging to the flavin-dependent amine oxidase family. Here, we report that AOF1 (KDM1B under the new nomenclature), a mammalian protein related to LSD1, also possesses histone demethylase activity with specificity for H3K4me1 and H3K4me2. Like LSD1, the highly conserved SWIRM domain is required for its enzymatic activity. However, AOF1 differs from LSD1 in several aspects. First, AOF1 does not appear to form stable protein complexes containing histone deacetylases. Second, AOF1 is found to localize to chromosomes during the mitotic phase of the cell cycle, whereas LSD1 does not. Third, AOF1 represses transcription when tethered to DNA and this repression activity is independent of its demethylase activity. Structural and functional analyses identified its unique N-terminal Zf-CW domain as essential for the demethylase activity-independent repression function. Collectively, our study identifies AOF1 as the second histone demethylase in the family of flavin-dependent amine oxidases and reveals a demethylase-independent repression function of AOF1.

| S-EPMC4106039 | biostudies-literature

RNA polymerase II progression through H3K27me3-enriched gene bodies requires JMJD3 histone demethylase.

Project description:JMJD3 H3K27me3 demethylase plays an important role in the transcriptional response to different signaling pathways; however, the mechanism by which it facilitates transcription has been unclear. Here we show that JMJD3 regulates transcription of transforming growth factor β (TGFβ)-responsive genes by promoting RNA polymerase II (RNAPII) progression along the gene bodies. Using chromatin immunoprecipitation followed by sequencing experiments, we show that, upon TGFβ treatment, JMJD3 and elongating RNAPII colocalize extensively along the intragenic regions of TGFβ target genes. According to these data, genome-wide analysis shows that JMJD3-dependent TGFβ target genes are enriched in H3K27me3 before TGFβ signaling pathway activation. Further molecular analyses demonstrate that JMJD3 demethylates H3K27me3 along the gene bodies, paving the way for the RNAPII progression. Overall these findings uncover the mechanism by which JMJD3 facilitates transcriptional activation.

| S-EPMC3564542 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data