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【論文摘要】Genes and Regulatory Pathways Potentially Responsible for Foam Cell Formation (Transcriptome Analysis)
摘要
Background/Synopsis: The accumulation of lipid-laded macrophages (foam cells) in the arterial wall is an earliest step in pathogenesis of atherosclerosis. It is generally accepted that the main sources of accumulating cholesterol in foam cells are atherogenic modified low-density lipoproteins (LDL) taking up by macrophages in an unregulated manner bypassing the specialized LDL receptor. Objectives/Purpose: In this study, we used a transcriptomic analysis (RNA-seq) to identify the genes and regulatory pathways potentially responsible for the accumulation of cholesterol in human monocytederived macrophages exposed to artificially modified or naturally occurring circulating atherogenic LDL particles. Methods/Results: We applied the data analysis pipeline 〞My-genome-enhancer〞 to this data set that contained RNA-seq raw files. The goal of this pipeline is to identify master regulators in gene regulatory networks of the studied pathological process. In the first step of analysis, the pipeline identifies differentially expressed genes (DEGs) and searches for potential genomic enhancers in the 5' regions of these gens and discover transcription factors (TFs) that regulate genes in response to stimulations by various modified or atherogenic LDL as well as by latex particles. In the second step of analysis, the pipeline performs the search for so-called master-regulators, which control transcription factors that were found in the first step. The most promising master-regulators are chosen as potentially responsible for the activation of the regulatory networks in the studied conditions. Finally, workflow comes up with the lists of top-10 master regulators and respective activated regulatory networks after exposure of the monocytederived macrophages to various stimuli. Our analysis of the regulatory regions of DEGs revealed the following TFs: NF-kBm, Nanog, KLF-4, PAX family and p53 as potentially involved in the regulation of the DEGs in our study. These TFs are known as playing important regulatory roles in immune response, inflammation, apoptosis and cell cycle control. Conclusion: The results of this analysis helped us to better understand the molecular mechanisms of the studied pathological process and identify promising drug targets for future studies. This work was supported by the Russian Science Foundation (Grant # 19-15-00010).
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