Abstract
BackgroundRetinol (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.ResultsBy 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.ConclusionsWe 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.
Highlights
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
A meta-analysis of the effects of retinoic acid on gene expression in different vertebrate tissues The results of all differentially expressed (DE) analyses are summarized in Additional file 2
DE analysis of the datasets by comparing untreated with RA treated cells or tissues led to the discovery of 139 DE genes in LMH cells (73.4% upregulated), 164 DE genes in SH-SY5Y cells (68.9% upregulated), 3967 DE genes in murine embryonic stem cells (mESCs) (56.8% upregulated), 679 DE genes in murine lymphocytes (57.4% upregulated), and 48 DE genes in Xenopus
Summary
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 increase species and cell-type diversity we generated RNA-seq data with chicken hepatocellular carcinoma (LMH) cells. Derivatives of RO, termed retinoids, are involved in cell proliferation, differentiation, cell adhesion, and apoptosis in different types of vertebrate tissues [1] and play an important role in immunity (reviewed in [2]), male and female reproduction, embryonic development, and barrier integrity (reviewed in [3]). RA binds to different nuclear receptors that regulate gene expression through the binding to certain canonical sequences termed retinoic acid response-elements (RAREs).
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