SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell

Fujimaki, Kyoko; Ogihara, Takeshi; Morris, David L.; Oda, Hisanobu; Iida, Hitoshi; Fujitani, Yoshio; Mirmira, Raghavendra G.; Evans‐Molina, Carmella; Watada, Hirotaka

doi:10.1074/jbc.m115.661777

Cited by 23 publications

(12 citation statements)

References 44 publications

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“…Li et al [30] have shown that histone methyltransferase SET7/9 contributes to TNFa-induced transcription of MCP-1 by promoting sitespecific histone H3K4 trimethylation in macrophages, similar to what we have shown for ASH2. This observation has been further corroborated by Fujimaki et al [31] who showed that SET7/9 regulates TNF-ainduced transactivation of iNOS, another NF-jB target, in islet b cells. Various studies have also placed MLL4 [32] or MLL1 [33] at the center of proinflammatory transcription in macrophages.…”

Section: Discussionsupporting

confidence: 68%

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MKL1 is an epigenetic mediator of TNF‐α‐induced proinflammatory transcription in macrophages by interacting with ASH2

et al. 2017

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Tumor necrosis factor alpha (TNF-α) is a prototypical proinflammatory cytokine that can elicit strong inflammation in macrophages by activating NF-κB. The underlying epigenetic mechanism is obscure. We show here that megakaryocytic leukemia 1 (MKL1) is an epigenetic mediator of TNF-α-induced proinflammatory transcription. Overexpression of a dominant negative form of MKL1 abrogates TNF-α-induced transactivation of proinflammatory genes. Proteomic analysis identifies the histone H3K4 trimethyltransferase ASH2 as a potential cofactor for MKL1. In response to TNF-α stimulation, ASH2 is recruited by MKL1 and interacts with MKL1 to catalyze H3K4 di- and trimethylation. ASH2 modulates proinflammatory transcription at least in part by altering the affinity of p65 for target promoters. Together, our data support an interplay between MKL1 and ASH2 to promote TNF-α-induced proinflammatory transcription in macrophages.

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Section: Discussionsupporting

confidence: 68%

“…This observation has been further corroborated by Fujimaki et al . who showed that SET7/9 regulates TNF‐α‐induced transactivation of iNOS, another NF‐κB target, in islet β cells. Various studies have also placed MLL4 or MLL1 at the center of proinflammatory transcription in macrophages.…”

Section: Discussionmentioning

confidence: 99%

MKL1 is an epigenetic mediator of TNF‐α‐induced proinflammatory transcription in macrophages by interacting with ASH2

et al. 2017

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“…As monomethylation at histone 3 lysine 4 by SET7/9 is generally associated with transcriptional activation 23,24 , we first focused our attention on the functional significance of SET7/9. The genome-wide transcriptional targets of SET7/9 were analyzed by chromatin immunoprecipitation-based deep sequencing (ChIP-seq) in MCF-7 cells.…”

Section: Identification Of Genome-wide Transcription Targets For Set7/9mentioning

confidence: 99%

SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21

Zhou

Zhao

et al. 2020

Cell Death Dis

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Although the deregulation of lysine methyltransferase (su(var)-3-9, enhancer-of-zeste, trithorax) domain-containing protein 7/9 (SET7/9) has been identified in a variety of cancers, the potential role of SET7/9 and the molecular events in which it is involved in breast cancer remain obscure. Using the online Human Protein Atlas and GEO databases, the expression of SET7/9 was analyzed. Furthermore, we investigated the underlying mechanisms using chromatin immunoprecipitation-based deep sequencing (ChIP-seq) and quantitative ChIP assays. To explore the physiological role of SET7/9, functional analyses such as CCK-8, colony formation, and transwell assays were performed and a xenograft tumor model was generated with the human breast cancer cell lines MCF-7 and MDA-MB-231. Mass spectrometry, co-immunoprecipitation, GST pull-down, and ubiquitination assays were used to explore the mechanisms of SET7/9 function in breast cancer. We evaluated the expression of SET7/9 in different breast cancer cohorts and found that higher expression indicated worse survival times in these public databases. We demonstrated positive effects of SET7/9 on cell proliferation, migration, and invasion via the activation of Runt-related transcription factor 2 (RUNX2). We demonstrate that tripartite motif-containing protein 21 (TRIM21) physically associates with SET7/9 and functions as a major negative regulator upstream of SET7/9 through a proteasome-dependent mechanism and increased ubiquitination. Taken together, our data suggest that SET7/9 has a promoting role via the regulation of RUNX2, whereas TRIM21-mediated SET7/9 degradation acts as an anti-braking system in the progression of breast cancer.

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“…Although, this did significantly reduce IFNγ, Il-1β, and TNFα-induced expression of Ccl2 , Ccl20 , Cxcl10 , Cxcl9 , and Il-15 , these reductions were relatively modest (1.8 to 3.6 fold). This suggests that the level of Wdr5 suppression achieved (only ~50% at the protein level) was not sufficient to completely block TrxG complex activity, or that other H3K4 methyltransferases independent of the TrxG complex, such as Setd7 [ 66 , 67 ], are involved. As an alternative approach we chose to use the small molecule inhibitor GSK-J4, which is converted intracellularly into GSK-J1, a potent inhibitor of Jmjd3 and Utx [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

The TrxG Complex Mediates Cytokine Induced De Novo Enhancer Formation in Islets

et al. 2015

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To better understand how β-cells respond to proinflammatory cytokines we mapped the locations of histone 3 lysine 4 monomethylation (H3K4me1), a post-translational histone modification enriched at active and poised cis-regulatory regions, in IFNγ, Il-1β, and TNFα treated pancreatic islets. We identified 96,721 putative cis-regulatory loci, of which 3,590 were generated de novo, 3,204 had increased H3K4me1, and 5,354 had decreased H3K4me1 in IFNγ, Il-1β, and TNFα exposed islets. Roughly 10% of the de novo and increased regions were enriched for the repressive histone modification histone 3 lysine 27 trimethylation (H3K27me3) in untreated cells, and these were frequently associated with chemokine genes. We show that IFNγ, Il-1β, and TNFα exposure overcomes this repression and induces chemokine gene activation in as little as three hours, and that this expression persists for days in absence of continued IFNγ, Il-1β, and TNFα exposure. We implicate trithorax group (TrxG) complexes as likely players in the conversion of these repressed loci to an active state. To block the activity of these complexes, we suppressed Wdr5, a core component of the TrxG complexes, and used the H3K27me3 demethylase inhibitor GSK-J4. We show that GSK-J4 is particularly effective in blunting IFNγ, Il-1β, and TNFα-induced chemokine gene expression in β-cells; however, it induced significant islet-cell apoptosis and β-cell dysfunction. Wdr5 suppression also reduced IFNγ, Il-1β, and TNFα induced chemokine gene expression in β-cells without affecting islet-cell survival or β-cell function after 48hrs, but did begin to increase islet-cell apoptosis and β-cell dysfunction after four days of treatment. Taken together these data suggest that the TrxG complex is potentially a viable target for preventing cytokine induced chemokine gene expression in β-cells.

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SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell

Cited by 23 publications

References 44 publications

MKL1 is an epigenetic mediator of TNF‐α‐induced proinflammatory transcription in macrophages by interacting with ASH2

MKL1 is an epigenetic mediator of TNF‐α‐induced proinflammatory transcription in macrophages by interacting with ASH2

SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21

The TrxG Complex Mediates Cytokine Induced De Novo Enhancer Formation in Islets

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