Supplementary data from: Role of endothelial micronuclei-contained DNA in atherosclerosis

Zitation: Natarelli, Lucia und Kichi, Zahra Abedi und Mann Fallenbuchel, Elizabeth Josefina und Parca, Luca und Mazza, Tommaso und Weber, Christian: Supplementary data from: Role of endothelial micronuclei-contained DNA in atherosclerosis. 22. Dezember 2022. Open Data LMU. 10.5282/ubm/data.352

Be­schrei­bung

Atherosclerosis is a complex disease that is often associated with hyperlipidaemia and affects the vessel tree under altered haemodynamic forces. However, shear stress is not itself responsible for the pathogenesis of atherosclerosis. Chromosomal mutations and DNA damage have emerged as key epigenetic signatures responsible for regional phenotypic heterogeneity, particularly in the endothelial cells (ECs) lining the arterial tree. We have previously reported that aortic ECs have a physiological tendency to accumulate damage in micronuclei (MN), which are usually generated in hyperproliferative cells. Hyperlipidaemia exacerbates DNA damage and MN formation in these ECs, but the interplay between endothelial MN and atherosclerosis is unknown. Here, we showed that low shear stress physiologically promoted MN formation in proliferative human ECs, whereas hyperlipidaemia enhanced the formation of pathological MN with DNA damage (pathological). DNA signatures were investigated by WGS of MN and the main nuclei containing DNA in synthesis or damaged. Duplications of known atherosclerosis susceptibility loci were found in physiological MN. Pathological MN contain duplications of pro-inflammatory genes, and mutations in cell cycle checkpoint and DNA damage repair genes. The transcriptional relevance of all key DNA damage repair markers of homologous recombination was confirmed. Hyperlipidaemia enhanced the accumulation of MN with defects in lamin B1, which is involved in double strand break repair through relocating damaged DNA at the nuclear periphery. Together, our findings indicated a role of DNA signatures that are relocated to endothelial MN in atherosclerosis and accumulate under impaired DNA repair.

Keywords

atherosclerosis, DNA damage, endothelial cells, micronuclei

Referenzen

References 1. Hong YM. Atherosclerotic cardiovascular disease beginning in childhood. Korean Circulation Journal. 2010;40(1):1-9. 2. Allam AH, Thompson RC, Wann LS, Miyamoto MI, Nur El-Din Ael H, El-Maksoud GA, et al. Atherosclerosis in ancient Egyptian mummies: The Horus study. JACC Cardiovascular Imaging. 2011;4(4):315-27. 3. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(1):12-22. 4. Natarelli L, Schober A. MicroRNAs and the response to injury in atherosclerosis. Hamostaseologie. 2015;35(2):142-50. 5. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524-33. 6. Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012;482(7383):53-8. 7. Natarelli L, Geißler C, Csaba G, Wei Y, Zhu M, di Francesco A, et al. miR-103 promotes endothelial maladaptation by targeting lncWDR59. Nat Commun. 2018;9(1):2645. 8. Uryga A, Gray K, Bennett M. DNA damage and repair in vascular disease. Annual Review of Physiology. 2016;78(1):45-66. 9. Shimizu N. Molecular mechanisms of the origin of micronuclei from extrachromosomal elements. Mutagenesis. 2011;26(1):119-23. 10. Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, et al. Chromothripsis from DNA damage in micronuclei. Nature. 2015;522(7555):179-84. 11. HEINLOTH A, HEERMEIER K, RAFF U, WANNER C, GALLE J. Stimulation of NADPH oxidase by oxidized low-density lipoprotein induces proliferation of human vascular endothelial cells. Journal of the American Society of Nephrology. 2000;11(10):1819-25. 12. Liu H, Zhang H, Wu X, Ma D, Wu J, Wang L, et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature. 2018;563(7729):131-6. 13. Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548(7668):461-5. 14. Schober A, Nazari-Jahantigh M, Wei Y, Bidzhekov K, Gremse F, Grommes J, et al. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nature medicine. 2014;20(4):368-76. 15. Uxa S, Castillo-Binder P, Kohler R, Stangner K, Müller GA, Engeland K. Ki-67 gene expression. Cell Death & Differentiation. 2021;28(12):3357-70. 16. Lusis AJ. Genetics of atherosclerosis. Trends in Genetics : TIG. 2012;28(6):267-75. 17. Palozola KC, Donahue G, Liu H, Grant GR, Becker JS, Cote A, et al. Mitotic transcription and waves of gene reactivation during mitotic exit. Science. 2017;358(6359):119-22. 18. Yue X, Bai C, Xie D, Ma T, Zhou P-K. DNA-PKcs: A multi-faceted player in DNA damage response. Frontiers in Genetics. 2020;11. 19. Maréchal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013;5(9):a012716. 20. Lamm N, Rogers S, Cesare AJ. Chromatin mobility and relocation in DNA repair. Trends in Cell Biology. 2021;31(10):843-55. 21. Kramarz K, Schirmeisen K, Boucherit V, Ait Saada A, Lovo C, Palancade B, et al. The nuclear pore primes recombination-dependent DNA synthesis at arrested forks by promoting SUMO removal. Nature Communications. 2020;11(1):5643. 22. Mahmoudi M, Gorenne I, Mercer J, Figg N, Littlewood T, Bennett M. Statins use a novel Nijmegen breakage syndrome-1-dependent pathway to accelerate DNA repair in vascular smooth muscle cells. Circulation Research. 2008;103(7):717-25. 23. Hartmann P, Zhou Z, Natarelli L, Wei Y, Nazari-Jahantigh M, Zhu M, et al. Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4. Nat Commun. 2016;7:10521. 24. Rausch T, Zichner T, Schlattl A, Stütz AM, Benes V, Korbel Jo. Delly: Structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28(18):i333-i9. 25. Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, et al. Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013;14:128. 26. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Research. 2016;44(W1):W90-7. 27. Xie Z, Bailey A, Kuleshov MV, Clarke DJB, Evangelista JE, Jenkins SL, et al. Gene set knowledge discovery with Enrichr. Current Protocols. 2021;1(3):e90.

• Dokumententyp: Daten
• Name der Kontakt­person: Natarelli, Lucia
• E-Mail der Kontaktperson: lucia.natarelli at med.uni-muenchen.de
• Fakultät: Medizinische Fakultät ; Fakultät für Biologie
• Dewey Dezimal­klassi­fikation: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie ; 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ID-Code: 352
• Hochgeladen von: Dr. Lucia Natarelli
• Hochgeladen am: 23. Dez. 2022 10:24