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BMC Genomics
2021 Mar 02;221:146. doi: 10.1186/s12864-021-07451-2.
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Multi-species transcriptome meta-analysis of the response to retinoic acid in vertebrates and comparative analysis of the effects of retinol and retinoic acid on gene expression in LMH cells.
Falker-Gieske C
,
Mott A
,
Franzenburg S
,
Tetens J
.
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BACKGROUND: Retinol (RO) and its active metabolite retinoic acid (RA) are major regulators of gene expression in vertebrates and influence various processes like organ development, cell differentiation, and immune response. To characterize a general transcriptomic response to RA-exposure in vertebrates, independent of species- and tissue-specific effects, four publicly available RNA-Seq datasets from Homo sapiens, Mus musculus, and Xenopus laevis were analyzed. To increase species and cell-type diversity we generated RNA-seq data with chicken hepatocellular carcinoma (LMH) cells. Additionally, we compared the response of LMH cells to RA and RO at different time points.
RESULTS: By conducting a transcriptome meta-analysis, we identified three retinoic acid response core clusters (RARCCs) consisting of 27 interacting proteins, seven of which have not been associated with retinoids yet. Comparison of the transcriptional response of LMH cells to RO and RA exposure at different time points led to the identification of non-coding RNAs (ncRNAs) that are only differentially expressed (DE) during the early response.
CONCLUSIONS: We propose that these RARCCs stand on top of a common regulatory RA hierarchy among vertebrates. Based on the protein sets included in these clusters we were able to identify an RA-response cluster, a control center type cluster, and a cluster that directs cell proliferation. Concerning the comparison of the cellular response to RA and RO we conclude that ncRNAs play an underestimated role in retinoid-mediated gene regulation.
Fig. 1. Volcano plot of differentially expressed genes from a transcriptome meta-analysis that was conducted with MetaVolcanoR. The results of each respective differential expression analysis from chicken hepatocellular carcinoma (LMH) cells, human neuroblastoma cells (SHSY5Y), murine embryonic stem cells (mESCs), murine lymphoblasts (mLympho), and in vitro-generated pancreatic explants from Xenopus laevis (Xenopus) after exposure to retinoic acid were used as input data. Red dots represent transcripts with a p-value < 0.02 and a LFC > 1
Fig. 2. Protein interaction analysis of differentially expressed genes from a transcriptome meta-analysis that was conducted with differential expression data from chicken hepatocellular carcinoma cells, human neuroblastoma cells, murine embryonic stem cells, murine lymphoblasts, and in vitro-generated pancreatic explants from Xenopus laevis after exposure to retinoic acid . DE genes with p-values < 0.02 and LFC > 1 were used for the analysis
Fig. 3. Gene cluster analysis of differentially expressed genes from a transcriptome meta-analysis that was conducted with differential expression data from chicken hepatocellular carcinoma cells, human neuroblastoma cells, murine embryonic stem cells, murine lymphoblasts, and in vitro-generated pancreatic explants from Xenopus laevis after exposure to retinoic acid. DE genes with a p-value < 0.05 and an abs. LFC > 0.5 were used for the analysis. a GO biological processes, b GO cellular components, c GO molecular functions, and d KEGG pathways
Fig. 4. Venn diagram of differentially expressed genes in LMH cells after exposure to retinoic acid for 1 h (RA_1h), retinoic acid for 4 h (RA_4h), retinol for 1 h (RO_1h), and retinol for 4 h (RO_4h)
Fig. 5. Heatmap of DE genes that differ between retinoic acid and retinol treatment in LMH cells: Log(FPKM) values of genes with at least 1.2-fold difference in FPKM values between retinoic acid and retinol treatment after 1 h or 4 h hours are shown. Cells treated with retinoic acid for 1 h (RA_1h), were compared with cell treated with retinol for 1 h (RO_1h) and cells treated with retinoic acid for 4 h (RA_4h), were compared with cell treated with retinol for 4 h (RO_4h)
Fig. 6. Gene cluster comparison of differentially expressed genes in LMH cells with clusterProfiler after exposure to retinoic acid for 1 h (RA_1h), retinoic acid for 4 h (RA_4h), retinol for 1 h (RO_1h), and retinol for 4 h (RO_4h). Sufficient differentially expressed genes were found to analyze a GO biological processes, b GO molecular functions, and c KEGG pathways
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