Astronauts Plasma-Derived Exosomes Induced Aberrant EZH2-Mediated H3K27me3 Epigenetic Regulation of the Vitamin D Receptor

Frontiers in Cardiovascular Medicine

article

Malik Bisserier¹  Agnieszka Brojakowska¹  Nathaniel Saffran¹  Amit Kumar Rai²  Brooke Lee²  Matthew Coleman³  Aimy Sebastian³  Angela Evans³  Paul J. Mills⁵  Sankar Addya⁶  Arsen Arakelyan⁷  Venkata Naga Srikanth Garikipati²  Lahouaria Hadri¹  David A. Goukassian¹ 

[1] Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute;Department of Emergency Medicine, The Ohio State University Wexner Medical Center;Lawrence Livermore National Laboratory;Department of Radiation Oncology, University of California;Center of Excellence for Research and Training in Integrative Health, University of California;Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University;Bioinformatics Group, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia;Department of Bioengineering, Bioinformatics, and Molecular Biology, Russian-Armenian University;Dorothy M. Davis Heart Lung and Research Institute, The Ohio State University Wexner Medical Center

关键词: astronauts;    spaceflight;    EZH2;    vitamin D receptor;    small extracellular vesicles;    epigenetic;   

DOI  :  10.3389/fcvm.2022.855181

学科分类：地球科学(综合)

来源: Frontiers

【 摘 要 】

There are unique stressors in the spaceflight environment. Exposure to such stressors may be associated with adverse effects on astronauts' health, including increased cancer and cardiovascular disease risks. Small extracellular vesicles (sEVs, i.e., exosomes) play a vital role in intercellular communication and regulate various biological processes contributing to their role in disease pathogenesis. To assess whether spaceflight alters sEVs transcriptome profile, sEVs were isolated from the blood plasma of 3 astronauts at two different time points: 10 days before launch (L-10) and 3 days after return (R+3) from the Shuttle mission. AC16 cells (human cardiomyocyte cell line) were treated with L-10 and R+3 astronauts-derived exosomes for 24 h. Total RNA was isolated and analyzed for gene expression profiling using Affymetrix microarrays. Enrichment analysis was performed using Enrichr. Transcription factor (TF) enrichment analysis using the ENCODE/ChEA Consensus TF database identified gene sets related to the polycomb repressive complex 2 (PRC2) and Vitamin D receptor (VDR) in AC16 cells treated with R+3 compared to cells treated with L-10 astronauts-derived exosomes. Further analysis of the histone modifications using datasets from the Roadmap Epigenomics Project confirmed enrichment in gene sets related to the H3K27me3 repressive mark. Interestingly, analysis of previously published H3K27me3–chromatin immunoprecipitation sequencing (ChIP-Seq) ENCODE datasets showed enrichment of H3K27me3 in the VDR promoter. Collectively, our results suggest that astronaut-derived sEVs may epigenetically repress the expression of the VDR in human adult cardiomyocytes by promoting the activation of the PRC2 complex and H3K27me3 levels.

【 授权许可】

CC BY