Human 5-lipoxygenase regulates transcription by association to euchromatin

[Display omitted] 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 regu...

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Published in:Biochemical pharmacology 2022-09, Vol.203, p.115187-115187, Article 115187
Main Authors: Kreiß, Marius, Oberlis, Julia H., Seuter, Sabine, Bischoff-Kont, Iris, Sürün, Duran, Thomas, Dominique, Göbel, Tamara, Schmid, Tobias, Rådmark, Olof, Brandes, Ralf P., Fürst, Robert, Häfner, Ann-Kathrin, Steinhilber, Dieter
Format: Article
Language:English
Subjects:
5-lipoxygenase
ChIP-Seq
FAIRE-Seq
Medicin och hälsovetenskap
RNA-Seq
Transcriptional regulation
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Summary:[Display omitted] 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.
ISSN:0006-2952
1873-2968
1873-2968
DOI:10.1016/j.bcp.2022.115187