Human 5-lipoxygenase regulates transcription by association to euchromatin

  • 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.

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Metadaten
Author:Marius KreißGND, Julia H. Oberlis, Sabine SeuterORCiDGND, Iris Bischoff-KontORCiDGND, Duran SürünORCiDGND, Dominique Jeanette ThomasORCiDGND, Tamara GöbelORCiD, Tobias SchmidORCiDGND, Olof RådmarkORCiD, Ralf BrandesORCiDGND, Robert FürstORCiDGND, Ann-Kathrin HäfnerORCiDGND, Dieter SteinhilberORCiDGND
URN:urn:nbn:de:hebis:30:3-784047
DOI:https://doi.org/10.1016/j.bcp.2022.115187
ISSN:0006-2952
Parent Title (English):Biochemical Pharmacology
Publisher:Elsevier
Place of publication:Amsterdam
Document Type:Article
Language:English
Date of Publication (online):2022/07/29
Date of first Publication:2022/07/22
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/08/09
Tag:5-lipoxygenase; ChIP-Seq; FAIRE-Seq; RNA-Seq; Transcriptional regulation
Volume:203
Issue:115187
Article Number:115187
Page Number:19
HeBIS-PPN:520852818
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International