Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cells link environmental fluctuations, such as nutrition, to metabolic remodeling. Epigenetic factors are thought to be involved in such cellular processes, but the molecular basis remains unclear. Here we report that the lysine-specific demethylase 2 (LSD2) suppresses the flux and metabolism of lipids to maintain the energy balance in hepatic cells. Using transcriptome and chromatin immunoprecipitation-sequencing analyses, we revealed that LSD2 represses the genes involved in lipid influx and metabolism through demethylation of histone H3K4. Selective recruitment of LSD2 at lipid metabolism gene loci was mediated in part by a stress-responsive transcription factor, c-Jun. Intriguingly, LSD2 depletion increased the intracellular levels of many lipid metabolites, which was accompanied by an increased susceptibility to toxic cell damage in response to fatty acid exposure. Our data demonstrate that LSD2 maintains metabolic plasticity under fluctuating environment in hepatocytes by mediating the cross talk between the epigenome and metabolism.
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PMID:Lysine-specific demethylase 2 suppresses lipid influx and metabolism in hepatic cells. 2562 47

Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.
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PMID:Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation. 2869 45

Endothelium-derived colony stimulating factor (CSF1) plays a key role in a range of human pathologies. Angiotensin II (Ang II) has been documented to stimulate CSF1 transcription although the underlying epigenetic mechanism remains unclear. Here we report that induction of CSF1 transcription by Ang II in vascular endothelial cells paralleled alterations of signature histone modifications surrounding the CSF1 promoter. Specifically, ChIP assays indicated that there was a simultaneous up-regulation of both acetylated H3 and trimethylated H3K4, indicative of transcriptional activation, and down-regulation of dimethyl H3K9, implicated in transcriptional repression, surrounding the proximal CSF1 promoter. Further analysis revealed that silencing of brahma related gene 1 (BRG1), a chromatin remodeling protein, abrogated CSF1 induction by Ang II. In the meantime, BRG1 silencing erased H3 acetylation and H3K4 trimethylation and restored H3K9 dimethylation. Mechanistically, BRG1 interacted with and recruited SET1A, a histone H3K4 methyltransferase, and JMJD1A, a histone H3K9 demethylase, to the CSF1 promoter to alter chromatin structure thereby promoting CSF1 trans-activation in response to Ang II stimulation. Knockdown of either SET1A or JMJD1A blocked CSF1 induction by Ang II. Finally, we demonstrate that the crosstalk between BRG1 and histone modifying enzymes was mediated by the transcription factor AP-1. In conclusion, our data unveil a novel epigenetic mechanism whereby a BRG1-centered complex mediates transcriptional activation of CSF1 by Ang II in vascular endothelial cells.
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PMID:Angiotensin II induced CSF1 transcription is mediated by a crosstalk between different epigenetic factors in vascular endothelial cells. 3031 27