Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
BMC Genomics
2021 Mar 02;221:146. doi: 10.1186/s12864-021-07451-2.
Show Gene links
Show Anatomy links
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
.
???displayArticle.abstract???
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
Al Tanoury,
Genes involved in cell adhesion and signaling: a new repertoire of retinoic acid receptor target genes in mouse embryonic fibroblasts.
2014, Pubmed
Al Tanoury,
Genes involved in cell adhesion and signaling: a new repertoire of retinoic acid receptor target genes in mouse embryonic fibroblasts.
2014,
Pubmed
Amann,
Regulation of gene expression by retinoids.
2011,
Pubmed
Antony,
Retrieval as a Fast Route to Memory Consolidation.
2017,
Pubmed
Babina,
Retinoic acid potentiates inflammatory cytokines in human mast cells: identification of mast cells as prominent constituents of the skin retinoid network.
2015,
Pubmed
Balmer,
Gene expression regulation by retinoic acid.
2002,
Pubmed
Bolger,
Trimmomatic: a flexible trimmer for Illumina sequence data.
2014,
Pubmed
Burney,
Retinoic acid syndrome: a potentially fatal side effect of retinoic acid therapy.
1998,
Pubmed
Burrows,
HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis.
2018,
Pubmed
Chee,
ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells.
2013,
Pubmed
Chen,
Characterization of the regulatory region of Adra2c, the gene encoding the murine alpha2C adrenoceptor subtype.
2004,
Pubmed
Churchman,
Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia.
2015,
Pubmed
Czernik,
Glucuronidation of estrogens and retinoic acid and expression of UDP-glucuronosyltransferase 2B7 in human intestinal mucosa.
2000,
Pubmed
Dickson,
Vitamin A and bone formation. Different responses to retinol and retinoic acid of chick bone cells in organ culture.
1989,
Pubmed
Doxakis,
Retinoic acid negatively regulates GDNF and neurturin receptor expression and responsiveness in embryonic chicken sympathetic neurons.
2005,
Pubmed
Duffy,
Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance.
2017,
Pubmed
Dulmage,
Lessons learned from gene expression profiling of cutaneous T-cell lymphoma.
2013,
Pubmed
Elias,
Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway.
2008,
Pubmed
Falker-Gieske,
Analysis of the brain transcriptome in lines of laying hens divergently selected for feather pecking.
2020,
Pubmed
Franzese,
Involvement of non-coding RNAs and transcription factors in the induction of Transglutaminase isoforms by ATRA.
2019,
Pubmed
Gere-Becker,
Retinoic acid-induced expression of Hnf1b and Fzd4 is required for pancreas development in Xenopus laevis.
2018,
Pubmed
,
Xenbase
Guo,
A Systematic Analysis Revealed the Potential Gene Regulatory Processes of ATRA-Triggered Neuroblastoma Differentiation and Identified a Novel RA Response Sequence in the NTRK2 Gene.
2020,
Pubmed
Haeseleer,
Molecular characterization of a novel short-chain dehydrogenase/reductase that reduces all-trans-retinal.
1998,
Pubmed
Harada,
Retinoic acid-inducible G protein-coupled receptors bind to frizzled receptors and may activate non-canonical Wnt signaling.
2007,
Pubmed
,
Xenbase
Harel,
Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: an unusual clinical picture.
2015,
Pubmed
Henning,
Retinoid receptors in bone and their role in bone remodeling.
2015,
Pubmed
Herzog,
The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor.
2007,
Pubmed
Hsu,
Synaptic retinoic acid receptor signaling mediates mTOR-dependent metaplasticity that controls hippocampal learning.
2019,
Pubmed
Hu,
Retinoic acid increases proliferation of human osteoclast progenitors and inhibits RANKL-stimulated osteoclast differentiation by suppressing RANK.
2010,
Pubmed
Isoherranen,
Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases.
2019,
Pubmed
Iyer,
Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18.
2020,
Pubmed
Janesick,
Retinoic acid signaling and neuronal differentiation.
2015,
Pubmed
Kam,
Retinoic acid synthesis and functions in early embryonic development.
2012,
Pubmed
Kathiriya,
Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism.
2004,
Pubmed
Katsushima,
Contribution of microRNA-1275 to Claudin11 protein suppression via a polycomb-mediated silencing mechanism in human glioma stem-like cells.
2012,
Pubmed
Kessler,
Treatment of cutaneous T-cell lymphoma (mycosis fungoides) with 13-cis-retinoic acid.
1983,
Pubmed
Kong,
A comparative study of the effects of retinol and retinoic acid on histological, molecular, and clinical properties of human skin.
2016,
Pubmed
Lanciotti,
Retinoic acid inhibits phosphatidylinositol turnover only in RA-sensitive while not in RA-resistant human neuroblastoma cells.
1989,
Pubmed
Lawrence,
Software for computing and annotating genomic ranges.
2013,
Pubmed
Leid,
Multiplicity generates diversity in the retinoic acid signalling pathways.
1992,
Pubmed
Li,
The multifaceted nature of retinoid transport and metabolism.
2014,
Pubmed
Love,
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
2014,
Pubmed
Ma,
T-cell lymphomas, a challenging disease: types, treatments, and future.
2017,
Pubmed
Maden,
Retinoic acid in the development, regeneration and maintenance of the nervous system.
2007,
Pubmed
Mangelsdorf,
The RXR heterodimers and orphan receptors.
1995,
Pubmed
Mattei,
Assignment of the human hap retinoic acid receptor RAR beta gene to the p24 band of chromosome 3.
1988,
Pubmed
Mi,
PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools.
2019,
Pubmed
Moretti,
Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid.
2016,
Pubmed
Moutier,
Retinoic acid receptors recognize the mouse genome through binding elements with diverse spacing and topology.
2012,
Pubmed
Mukhopadhyay,
Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-gamma.
2010,
Pubmed
Napoli,
Microsomes convert retinol and retinal into retinoic acid and interfere in the conversions catalyzed by cytosol.
1990,
Pubmed
Nolte,
Hox genes: Downstream "effectors" of retinoic acid signaling in vertebrate embryogenesis.
2019,
Pubmed
Obrochta,
Insulin regulates retinol dehydrogenase expression and all-trans-retinoic acid biosynthesis through FoxO1.
2015,
Pubmed
Perreault,
Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction.
2013,
Pubmed
Pezzini,
Transcriptomic Profiling Discloses Molecular and Cellular Events Related to Neuronal Differentiation in SH-SY5Y Neuroblastoma Cells.
2017,
Pubmed
Pino-Lagos,
Retinoic acid: a key player in immunity.
2010,
Pubmed
Ponzoni,
Retinoic acid rapidly decreases phosphatidylinositol turnover during neuroblastoma cell differentiation.
1990,
Pubmed
Richard,
Identification of a retinoic acid response element in the human oxytocin promoter.
1991,
Pubmed
Roa,
Retinoic acid disrupts osteogenesis in pre-osteoblasts by down-regulating WNT signaling.
2019,
Pubmed
Rowbotham,
Role of UDP-glucuronosyltransferase isoforms in 13-cis retinoic acid metabolism in humans.
2010,
Pubmed
Rowland,
The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification.
2013,
Pubmed
Szklarczyk,
STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets.
2019,
Pubmed
Tang,
Retinoids, retinoic acid receptors, and cancer.
2011,
Pubmed
Tariq,
A case of life-threatening retinoic acid syndrome and review of literature.
2014,
Pubmed
Telgenhoff,
Claudin 2 mRNA and protein are present in human keratinocytes and may be regulated by all-trans-retinoic acid.
2008,
Pubmed
Terranova,
Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1).
2015,
Pubmed
Trapnell,
TopHat: discovering splice junctions with RNA-Seq.
2009,
Pubmed
Wei,
Retinoids and receptor interacting protein 140 (RIP140) in gene regulation.
2004,
Pubmed
White,
Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism.
2000,
Pubmed
Wu,
Cloning and characterization of a novel all-trans retinol short-chain dehydrogenase/reductase from the RPE.
2002,
Pubmed
Xu,
Inhibition of Proliferation by Knockdown of Transmembrane (TMEM) 168 in Glioblastoma Cells via Suppression of Wnt/β-Catenin Pathway.
2019,
Pubmed
Yamada,
Identification of twinfilin-2 as a factor involved in neurite outgrowth by RNAi-based screen.
2007,
Pubmed
Yorgan,
Immediate effects of retinoic acid on gene expression in primary murine osteoblasts.
2016,
Pubmed
Yu,
clusterProfiler: an R package for comparing biological themes among gene clusters.
2012,
Pubmed
van der Hem,
All-trans retinoic acid toxicity.
1992,
Pubmed