| Autor: |
Marius, Kreiß, Julia H, Oberlis, Sabine, Seuter, Iris, Bischoff-Kont, Duran, Sürün, Dominique, Thomas, Tamara, Göbel, Tobias, Schmid, Olof, Rådmark, Ralf P, Brandes, Robert, Fürst, Ann-Kathrin, Häfner, Dieter, Steinhilber |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Biochemical pharmacology. 203 |
| ISSN: |
1873-2968 |
| Popis: |
Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, besides its canonical function as an arachidonic acid metabolizing enzyme, is a regulator of gene expression associated with euchromatin. By Crispr-Cas9-mediated 5-LO knockout (KO) in MonoMac6 (MM6) cells and subsequent RNA-Seq analysis, we identified 5-LO regulated genes which could be clustered to immune/defense response, cell adhesion, transcription and growth/developmental processes. Analysis of differentially expressed genes identified cyclooxygenase-2 (COX2, PTGS2) and kynureninase (KYNU) as strongly regulated 5-LO target genes. 5-LO knockout affected MM6 cell adhesion and tryptophan metabolism via inhibition of the degradation of the immunoregulator kynurenine. By subsequent FAIRE-Seq and 5-LO ChIP-Seq analyses, we found an association of 5-LO with euchromatin, with prominent 5-LO binding to promoter regions in actively transcribed genes. By enrichment analysis of the ChIP-Seq results, we identified potential 5-LO interaction partners. Furthermore, 5-LO ChIP-Seq peaks resemble patterns of H3K27ac histone marks, suggesting that 5-LO recruitment mainly takes place at acetylated histones. In summary, we demonstrate a noncanonical function of 5-LO as transcriptional regulator in monocytic cells. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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