Transcriptional Regulation of 15-Lipoxygenase Expression by Histone H3 Lysine 4 Methylation/Demethylation

Abstract

15-Lipoxygenase-1 (15-LOX-1) oxidizes polyunsaturated fatty acids to a rich spectrum of biologically active metabolites and is implicated in physiological membrane remodelling, inflammation and apoptosis. Its deregulation is involved in the pathogenesis of diverse cancer and immune diseases. Recent experimental evidence reveals that dynamic histone methylation/demethylation mediated by histone methyltransferases and demethylases plays a critical role in regulation of chromatin remodelling and gene expression. In the present study, we compared the histone 3 lysine 4 (H3-K4) methylation status of the 15-LOX-1 promoter region of the two Hodgkin lymphoma (HL) cell lines L1236 and L428 with abundant and undetectable 15-LOX-1 expression, respectively. We identified a potential role of H3-K4 methylation in positive regulation of 15-LOX-1 transcription. Furthermore, we found that histone methyltransferase SMYD3 inhibition reduced 15-LOX-1 expression by decreasing promoter activity in L1236 cells. SMYD3 knock down in these cells abolished di−/trimethylation of H3-K4, attenuated the occupancy by the transactivator STAT6, and led to diminished histone H3 acetylation at the 15-LOX-1 promoter. In contrast, inhibition of SMCX, a JmjC-domain-containing H3-K4 tri-demethylase, upregulated 15-LOX-1 expression through induction of H3-K4 trimethylation, histone acetylation and STAT6 recruitment at the 15-LOX-1 promoter in L428 cells. In addition, we observed strong SMYD3 expression in the prostate cancer cell line LNCaP and its inhibition led to decreased 15-LOX-1 expression. Taken together, our data suggest that regulation of histone methylation/demethylation at the 15-LOX-1 promoter is important in 15-LOX-1 expression.

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“…Consistent with reports from cell culture and peripheral tissue, KMD5C loss also led to an accumulation of H3K4me3 (F (1,10) =5.99; P <0.05; Fig. 6D), extending its role as an H3K4 demethylase to the brain and indicating that KDM5C contributes to the active maintenance of H3K4me3 in the NAc (28, 46-50). …”

Cytokine Induced Phenotypic and Epigenetic Signatures Are Key to Establishing Specific Macrophage Phenotypes

“…We hypothesize that this is due to SMYD3 activity, as we found that SMYD3, another H3K4-methyltransferase, is preferentially expressed in M2 MΦ. Recently, SMYD3 has been shown to regulate 15-Lipoxygenase expression [45] which further supports the data from our experiments. However, M2 clearly displayed a lower methyltransferase activity than M1 MΦ, suggesting that a high H3K4-specific methyltransferase activity is indeed a feature of classical activation (Figure 7).…”

Changes in Histone Methylation and Acetylation during Microspore Reprogramming to Embryogenesis Occur Concomitantly with Bn<b><i>HKMT</i></b> and Bn<b><i>HAT</i></b> Expression and Are Associated with Cell Totipotency, Proliferation, and Differentiation in <b><i>Brassica napus</i></b>

“…In Arabidopsis , H3K9 methylation was found predominately as H3K9me1 and H3K9me2 in chromatin regions enriched in transposons and repeated sequences and associated with heterochromatin [Lippman et al, 2004]. The methylation marks of histones are generated by distinct enzymes named histone lysine methyltransferases (HKMTs) [Liu C et al, 2012]. Acetylation of lysines in histones has been recognized as a characteristic of actively transcribed genes by altering histone-DNA interactions and making the DNA more accessible to the transcription machinery [Xu et al, 2005;Earley et al, 2007].…”