Endothelial cells.Table S1 List of endothelial genes specifically ex-pressed in brain, heart and kidney glomeruli. (XLSX)Table S2 Full list of GWAS disease associated genes expressed in brain vasculome. The label “brain EC expressed” indicates whether the gene is expressed in brain vasculome (True) or not (False).Author ContributionsConceived and designed the experiments: SG YZ EHL. Performed the experiments: SG JL CX ATS. Analyzed the data: YZ EHL SG. Wrote the paper: SG YZ JL MMN XJ EHL.
15-LOX-1 is a peroxidase which catalyzes the oxygenation of free or membrane-bound polyunsaturated fatty acids containing at least one bis-allylic methylene [1]. It is implicated in various physiological processes including membrane remodelling, cell differentiation, inflammation and apoptosis [2,3]. Deregulation of 15-LOX-1 expression is suggested to be involved in the pathogenesis of diverse malignancies, including prostate and colorectal cancer [4,5], asthma [6,7], Finafloxacin atherosclerosis [8], orbital fibrosis [9] and nephritis [10]. Moreover, introduction of 15-LOX1 into cells could result in oxidative stress and membrane degradation [11,12]. Therefore, the expression and activity of the enzyme are strictly controlled. In most 15-LOX-1 inducible cell types, the enzyme is predominantly activated through the IL4/13-signal transducer and activator of transcription 6 (STAT6) cascade [13,14,15]. 15-LOX1 mRNA transcription is also associated with CpG island methylation status and FGF-401 biological activity histone acetylation status at the promoterlevel [16]. Different experimental evidences suggest that histone acetylation is positively correlated with 15-LOX-1 transcriptional activation [13,16,17,18,19]. In a previous study of HL cell lines we showed that DNA hyper-methylation is associated with silenced 15-LOX-1 transcription and that demethylation is required for 15LOX-1 transactivation [16]. However, it was recently reported that hypermethylation of specific CpG di-nucleotides in the 15LOX-1 promoter leads to the upregulation of 15-LOX-1 expression and enzyme activity in prostate cancer cells [20]. Moreover, recent work on colorectal cancer showed that 15-LOX1 promoter methylation levels did not significantly correlate with 15-LOX-1 mRNA expression levels in neither cancer cell lines 24195657 nor in the patients’ tumor specimens [21]. Therefore, additional epigenetic mechanism(s) could be involved in the transcriptional regulation of 15-LOX-1, controlling the tissue- and cell-type specific 15-LOX-1 gene expression. Lysine is the key substrate residue in histone methylation, which can occur one, two or three times (mono-, di- or trimethylation), leading to different biological outcomes. Histone methylationHistone Methylation Regulates 15-LOX-1 Expressioncould have various effects on gene transcription, depending on the precise residues and levels of methylation [22]. Generally, histone 3 lysine 4 (H3-K4) tri- and di- methylation have an activating effect on gene expression [22]. Histone methylation status of specific residues is an outcome of a dynamic balance between corresponding histone methyltransferases (HMTs) and histone demethylases(HDMs) [23]. HMTs are histone-lysine/arginine N-methyltransferases that catalyze the transfer of methyl groups to lysine/arginine residue of histones. Among the HMTs, SET and MYND domain-containing protein 3 (SMYD3) is a HMT that contains a SET domain and has histone H3-K4 di- or tri-methyltransferase activity [24]. SMYD3 is also a transcription factor tha.Endothelial cells.Table S1 List of endothelial genes specifically ex-pressed in brain, heart and kidney glomeruli. (XLSX)Table S2 Full list of GWAS disease associated genes expressed in brain vasculome. The label “brain EC expressed” indicates whether the gene is expressed in brain vasculome (True) or not (False).Author ContributionsConceived and designed the experiments: SG YZ EHL. Performed the experiments: SG JL CX ATS. Analyzed the data: YZ EHL SG. Wrote the paper: SG YZ JL MMN XJ EHL.
15-LOX-1 is a peroxidase which catalyzes the oxygenation of free or membrane-bound polyunsaturated fatty acids containing at least one bis-allylic methylene [1]. It is implicated in various physiological processes including membrane remodelling, cell differentiation, inflammation and apoptosis [2,3]. Deregulation of 15-LOX-1 expression is suggested to be involved in the pathogenesis of diverse malignancies, including prostate and colorectal cancer [4,5], asthma [6,7], atherosclerosis [8], orbital fibrosis [9] and nephritis [10]. Moreover, introduction of 15-LOX1 into cells could result in oxidative stress and membrane degradation [11,12]. Therefore, the expression and activity of the enzyme are strictly controlled. In most 15-LOX-1 inducible cell types, the enzyme is predominantly activated through the IL4/13-signal transducer and activator of transcription 6 (STAT6) cascade [13,14,15]. 15-LOX1 mRNA transcription is also associated with CpG island methylation status and histone acetylation status at the promoterlevel [16]. Different experimental evidences suggest that histone acetylation is positively correlated with 15-LOX-1 transcriptional activation [13,16,17,18,19]. In a previous study of HL cell lines we showed that DNA hyper-methylation is associated with silenced 15-LOX-1 transcription and that demethylation is required for 15LOX-1 transactivation [16]. However, it was recently reported that hypermethylation of specific CpG di-nucleotides in the 15LOX-1 promoter leads to the upregulation of 15-LOX-1 expression and enzyme activity in prostate cancer cells [20]. Moreover, recent work on colorectal cancer showed that 15-LOX1 promoter methylation levels did not significantly correlate with 15-LOX-1 mRNA expression levels in neither cancer cell lines 24195657 nor in the patients’ tumor specimens [21]. Therefore, additional epigenetic mechanism(s) could be involved in the transcriptional regulation of 15-LOX-1, controlling the tissue- and cell-type specific 15-LOX-1 gene expression. Lysine is the key substrate residue in histone methylation, which can occur one, two or three times (mono-, di- or trimethylation), leading to different biological outcomes. Histone methylationHistone Methylation Regulates 15-LOX-1 Expressioncould have various effects on gene transcription, depending on the precise residues and levels of methylation [22]. Generally, histone 3 lysine 4 (H3-K4) tri- and di- methylation have an activating effect on gene expression [22]. Histone methylation status of specific residues is an outcome of a dynamic balance between corresponding histone methyltransferases (HMTs) and histone demethylases(HDMs) [23]. HMTs are histone-lysine/arginine N-methyltransferases that catalyze the transfer of methyl groups to lysine/arginine residue of histones. Among the HMTs, SET and MYND domain-containing protein 3 (SMYD3) is a HMT that contains a SET domain and has histone H3-K4 di- or tri-methyltransferase activity [24]. SMYD3 is also a transcription factor tha.