GO:1900053 negative regulation of retinoic acid biosynthetic process: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1900053 describes any process that stops, prevents, or reduces the frequency, rate, or extent of retinoic acid (RA) biosynthesis, a critical control point in development, immunity, and cancer.
• Retinoic acid biosynthesis is a multistep enzymatic pathway; its negative regulation occurs at transcriptional, post-transcriptional, and feedback levels, often through retinoic acid receptors (RARs) and metabolic enzymes.
• Key genes involved include ALDH1A family members, CYP26 enzymes, CRABP1/2, RARs, and metabolic regulators such as MTHFD1 and WT1.
• Dysregulation of this process is linked to anencephaly, inflammation, stem cell niche maintenance, and cancer, making it a target for therapeutic intervention.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of negative regulatory mechanisms in vitro and in vivo.
• Studying GO:1900053 requires integrated approaches: gene editing, transcriptomics, metabolomics, and imaging to capture dynamic RA flux and regulatory feedback.
Description
Retinoic acid (RA) is a vitamin A-derived morphogen that controls gene expression programs essential for embryonic development, immune homeostasis, and tissue regeneration. The biosynthetic process that produces RA is tightly regulated; its negative regulation, formalized as GO:1900053, ensures that RA levels are kept within physiological bounds. This Gene Ontology term encompasses any mechanism that reduces the frequency, rate, or extent of RA biosynthesis, including feedback inhibition by RA itself, transcriptional repression of biosynthetic enzymes, and post-translational modifications. Understanding GO:1900053 is crucial because imbalances in RA biosynthesis underlie severe congenital defects, chronic inflammation, and cancer progression. Researchers studying this term aim to identify the molecular players and environmental cues that suppress RA production, and to manipulate them for therapeutic benefit. This article synthesizes authoritative QuickGO data and verified PubMed literature to provide a research-grade overview of the mechanisms, genes, and experimental models relevant to GO:1900053.
negative regulation of retinoic acid biosynthetic process At A Glance
| GO ID | GO:1900053 |
|---|---|
| GO term | negative regulation of retinoic acid biosynthetic process |
| Ontology | biological_process |
| Synonym | down regulation of retinoic acid anabolic process; inhibition of retinoic acid biosynthetic process; negative regulation of retinoic acid anabolic process |
| Major function | Suppresses the production of retinoic acid, a key signaling molecule in development and immunity |
| Related processes | Retinoic acid biosynthetic process (GO:0002138), retinoic acid metabolic process (GO:0002138), regulation of retinoic acid biosynthetic process (GO:1900052) |
| Key regulators | RARs, CYP26 enzymes, ALDH1A enzymes, CRABP1/2, MTHFD1, WT1 |
| Disease relevance | Anencephaly, inflammation, cancer, stem cell niche dysregulation |
What Is GO:1900053?
GO:1900053, negative regulation of retinoic acid biosynthetic process, is defined by QuickGO as any process that stops, prevents, or reduces the frequency, rate, or extent of retinoic acid biosynthetic process. In other words, it covers all biological events that downregulate the production of retinoic acid from its precursors, such as retinol and retinaldehyde. This regulation can occur at multiple levels: inhibition of enzymes like ALDH1A, induction of RA-degrading enzymes like CYP26, or feedback repression via retinoic acid receptors.
Why Is negative regulation of retinoic acid biosynthetic process Important in Cell Biology?
GO:1900053 is important because retinoic acid is a potent signaling molecule whose levels must be precisely controlled. Negative regulation prevents excessive RA signaling, which can lead to teratogenic effects, while also allowing rapid modulation of RA availability during development and immune responses. Disruption of this regulation is associated with neural tube defects like anencephaly, chronic inflammatory diseases, and cancer. Therefore, understanding the mechanisms of GO:1900053 provides insights into fundamental biology and offers targets for therapeutic intervention.
• Prevents teratogenic effects of excess retinoic acid during embryogenesis.
• Modulates immune responses by controlling RA availability in inflammation.
• Regulates stem cell niches, as shown in mouse incisor models.
• Influences spermatogenesis through Gdnf regulation in Sertoli cells.
• Contributes to systemic anti-inflammation via CRABP1-mediated exosome secretion.
• Involved in cancer biology through altered RA metabolism.
• Provides feedback control to maintain vitamin A homeostasis.
• Offers targets for CRISPR-based disease modeling and drug discovery.
What Happens During negative regulation of retinoic acid biosynthetic process?
Feedback Inhibition by Retinoic Acid
In simple terms: When too much retinoic acid is made, it can turn off its own production.
Retinoic acid can induce the expression of CYP26 enzymes, which degrade RA, and repress the expression of ALDH1A enzymes, which synthesize RA. This feedback loop is mediated by retinoic acid receptors (RARs) that bind to response elements in target genes. For example, RA treatment leads to negative regulation of NF-kappaB/miR-21 signaling, indirectly affecting RA biosynthesis.
Transcriptional Repression of Biosynthetic Enzymes
In simple terms: Certain proteins can block the genes that make retinoic acid.
Transcription factors such as WT1 and HDAC inhibitors regulate the expression of retinoic acid synthetic enzymes in 293 cells. MTHFD1 is critical for negative regulation of retinoic acid receptor signaling in anencephaly, linking one-carbon metabolism to RA biosynthesis suppression.
Post-transcriptional and Post-translational Control
In simple terms: Even after the instructions are made, the process can be stopped before retinoic acid is produced.
Cellular retinoic acid binding protein 1 (CRABP1) regulates exosome secretion, which contributes to systemic anti-inflammation and may affect RA availability. Additionally, negative regulation can occur through microRNAs and protein modifications that target biosynthetic enzymes.
Regulation of Stem Cell Niches
In simple terms: Retinoic acid levels affect how stem cells behave, and negative regulation keeps this in check.
In mouse incisor stem cell niches, negative effects of retinoic acid on stem cell maintenance have been observed, indicating that suppression of RA biosynthesis is necessary to preserve stemness. Similarly, in Sertoli cells, retinoic acid regulates Gdnf expression, which is important for spermatogonial stem cell maintenance.
Key Genes Involved in GO:1900053 negative regulation of retinoic acid biosynthetic process
The following genes and proteins are central to the negative regulation of retinoic acid biosynthetic process, based on verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ALDH1A1 | Retinaldehyde dehydrogenase; catalyzes RA synthesis | Target for negative regulation; knockout reduces RA |
| ALDH1A2 | Retinaldehyde dehydrogenase; major RA synthesizing enzyme | Feedback repression by RA |
| ALDH1A3 | Retinaldehyde dehydrogenase; RA synthesis in specific tissues | Regulated by WT1 and HDAC inhibitors |
| CYP26A1 | Cytochrome P450; degrades retinoic acid | Induced by RA as negative feedback |
| CYP26B1 | Cytochrome P450; degrades retinoic acid | Important in development and germ cells |
| CYP26C1 | Cytochrome P450; degrades retinoic acid | Feedback regulation |
| RARA | Retinoic acid receptor alpha; mediates feedback | Negative regulation of RA signaling |
| RARB | Retinoic acid receptor beta; mediates feedback | Negative side of RA receptors |
| RARG | Retinoic acid receptor gamma; mediates feedback | Negative regulation |
| CRABP1 | Cellular retinoic acid binding protein 1 | Regulates exosome secretion and anti-inflammation |
| CRABP2 | Cellular retinoic acid binding protein 2 | Intracellular RA transport |
| MTHFD1 | One-carbon metabolism enzyme | Critical for negative regulation of RAR signaling in anencephaly |
| WT1 | Wilms tumor 1 transcription factor | Regulates RA synthetic enzymes |
| HDAC1 | Histone deacetylase 1 | Inhibitors regulate RA synthetic enzymes |
| NF-kB | Inflammatory transcription factor | Negatively regulated by RA via miR-21 |
| GDNF | Glial cell line-derived neurotrophic factor | Regulated by RA in Sertoli cells |
| miR-21 | MicroRNA | Mediates RA negative regulation of NF-kB |
How Is negative regulation of retinoic acid biosynthetic process Regulated?
The negative regulation of retinoic acid biosynthetic process is itself regulated by multiple inputs. Retinoic acid levels are sensed by RARs, which upon ligand binding repress or activate target genes including CYP26 and ALDH1A. One-carbon metabolism, through MTHFD1, influences methylation and gene expression to suppress RAR signaling. Inflammatory signals can modulate RA biosynthesis via NF-kB/miR-21 feedback. Additionally, WT1 and HDAC inhibitors control the expression of RA synthetic enzymes. These layers ensure that RA production is finely tuned to developmental and environmental cues.
negative regulation of retinoic acid biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MTHFD1 | Anencephaly | Knockout mouse, neural tube organoids |
| CRABP1 | Systemic inflammation | Knockout mouse, macrophage cell lines |
| ALDH1A2 | Cancer, developmental defects | Point mutation knock-in, cancer cell lines |
| CYP26A1 | Teratogenicity, cancer | Overexpression, zebrafish models |
| RARA | Leukemia, developmental disorders | Knock-in fusion models, hematopoietic cells |
Anencephaly and Neural Tube Defects
MTHFD1 is critical for the negative regulation of retinoic acid receptor signaling in anencephaly, a severe neural tube defect. Disruption of this negative regulation leads to excessive RA signaling and impaired neural tube closure. This highlights the importance of GO:1900053 in embryonic development.
Inflammation and Immune Regulation
Retinoic acid abrogates LPS-induced inflammatory responses via negative regulation of NF-kappaB/miR-21 signaling. CRABP1 regulates exosome secretion, contributing to systemic anti-inflammation. Thus, negative regulation of RA biosynthesis is intertwined with immune homeostasis.
Cancer and Stem Cell Biology
Altered retinoic acid metabolism is observed in various cancers. Negative regulation of RA biosynthesis can promote stemness and tumorigenesis. In mouse incisor stem cell niches, RA negatively affects stem cell maintenance, suggesting that suppression of RA production is necessary for stem cell preservation.
Reproductive Biology
In Sertoli cells, retinoic acid regulates Gdnf expression, which is essential for spermatogonial stem cell maintenance. Negative regulation of RA biosynthesis may therefore impact male fertility.
From negative regulation of retinoic acid biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of MTHFD1 affect RA biosynthesis? | MTHFD1 knockout cell line |
| How does a point mutation in ALDH1A2 alter RA production? | ALDH1A2 point mutation knock-in |
| Can overexpression of CYP26A1 reduce RA levels? | CYP26A1 overexpression cell line |
| Where is CRABP1 localized during inflammation? | Tagged knock-in of CRABP1 |
| Does RAR feedback require specific response elements? | RAR knockout and reporter assays |
| What is the impact of WT1 on RA synthetic enzymes? | WT1 knockout and HDAC inhibitor treatment |
How to Study the negative regulation of retinoic acid biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Gene expression changes | Identify transcriptional regulators of RA biosynthesis |
| Metabolomics | RA and precursor levels | Quantify negative regulation of RA production |
| CRISPR knockout screening | Gene function loss | Discover novel negative regulators |
| ChIP-seq | Protein-DNA interactions | Map RAR binding sites in target genes |
| Reporter assays | RA signaling activity | Monitor feedback inhibition |
| Proteomics | Protein abundance and modifications | Identify post-translational regulation |
| Exosome analysis | Vesicle secretion | Study CRABP1-mediated anti-inflammation |
Transcriptomic Analysis
RNA-seq can quantify expression changes in RA biosynthetic and degradative enzymes upon genetic or pharmacological perturbation. This helps identify transcriptional networks underlying GO:1900053.
Metabolomic Profiling
Mass spectrometry-based metabolomics measures retinoic acid and its precursors directly, providing a functional readout of negative regulation.
CRISPR Screening
Genome-wide CRISPR knockout or activation screens can identify genes whose loss or gain affects RA levels, revealing novel regulators of GO:1900053.
Imaging and Reporter Assays
RA-responsive reporter cell lines and fluorescent probes allow real-time monitoring of RA signaling dynamics in live cells and tissues.
How CRISPR Can Be Used to Study GO:1900053 negative regulation of retinoic acid biosynthetic process
Knockout
CRISPR knockout of genes such as MTHFD1, ALDH1A2, or CYP26A1 can reveal their roles in negative regulation of RA biosynthesis. For example, MTHFD1 knockout leads to dysregulated RAR signaling in anencephaly models.
Point Mutation
Introducing point mutations in catalytic residues of ALDH1A enzymes or in RAR response elements can dissect specific mechanisms of negative regulation without completely abolishing protein function.
Knock-in
Knock-in of tagged versions of CRABP1 or CYP26A1 allows tracking of protein localization and dynamics, providing insights into how these proteins mediate negative regulation.
Overexpression
Overexpression of CYP26 enzymes or dominant-negative RARs can suppress RA biosynthesis, mimicking negative regulation and enabling studies of downstream effects.
How EDITGENE Supports negative regulation of retinoic acid biosynthetic process Research
Researchers studying negative regulation of retinoic acid biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in suppressing RA production. This requires precise genetic models that can knockout, mutate, knock-in, or overexpress the gene of interest. EDITGENE provides end-to-end CRISPR services to accelerate such discoveries.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of retinoic acid biosynthetic process research.
Frequently Asked Questions About negative regulation of retinoic acid biosynthetic process
What is GO:1900053?
GO:1900053 is the Gene Ontology term for negative regulation of retinoic acid biosynthetic process, describing any mechanism that reduces the production of retinoic acid.
What genes are involved in negative regulation of retinoic acid biosynthetic process?
Key genes include ALDH1A family, CYP26 enzymes, RARs, CRABP1/2, MTHFD1, and WT1.
How is retinoic acid biosynthesis negatively regulated?
Through feedback inhibition by RA, transcriptional repression of biosynthetic enzymes, and post-transcriptional mechanisms.
What diseases are associated with dysregulation of this process?
Anencephaly, inflammation, cancer, and stem cell disorders.
What experimental models are used to study GO:1900053?
CRISPR knockout, point mutation, knock-in, overexpression cell lines, and animal models.
How does MTHFD1 relate to retinoic acid regulation?
MTHFD1 is critical for negative regulation of retinoic acid receptor signaling in anencephaly.
Can CRISPR be used to study negative regulation of RA biosynthesis?
Yes, CRISPR knockout or overexpression of key genes can reveal their roles in suppressing RA production.
What is the role of CYP26 enzymes?
CYP26 enzymes degrade retinoic acid and are induced as part of negative feedback to reduce RA levels.
How does CRABP1 contribute to anti-inflammation?
CRABP1 regulates exosome secretion, which contributes to systemic anti-inflammation.
What methods measure retinoic acid levels?
Metabolomics, reporter assays, and RNA-seq of target genes.
Conclusion
GO:1900053, negative regulation of retinoic acid biosynthetic process, is a critical biological process that maintains retinoic acid homeostasis. Its dysregulation is implicated in severe developmental defects, inflammation, and cancer. Through the integration of CRISPR-based models, multi-omics, and bioinformatics, researchers can uncover the precise molecular mechanisms and identify therapeutic targets. EDITGENE offers comprehensive services to support these investigations, from gene editing to library screening.
References
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- 2. Linney E et al.. 2011. The negative side of retinoic acid receptors.. Neurotoxicol Teratol 33(6):631-40 PMID: 21767634
- 3. Nurrahmah QI et al.. 2021. Retinoic acid abrogates LPS-induced inflammatory response via negative regulation of NF-kappa B/miR-21 signaling.. Immunopharmacol Immunotoxicol 43(3):299-308 PMID: 33757404
- 4. Saracino R et al.. 2020. Regulation of Gdnf expression by retinoic acid in Sertoli cells.. Mol Reprod Dev 87(4):419-429 PMID: 32020743
- 5. Xi J et al.. 2016. Negative effects of retinoic acid on stem cell niche of mouse incisor.. Stem Cell Res 17(3):489-497 PMID: 27771497
- 6. Lin YW et al.. 2021. Regulation of exosome secretion by cellular retinoic acid binding protein 1 contributes to systemic anti-inflammation.. Cell Commun Signal 19(1):69 PMID: 34193153
- 7. Li Y et al.. 2017. Regulation of retinoic acid synthetic enzymes by WT1 and HDAC inhibitors in 293 cells.. Int J Mol Med 40(3):661-672 PMID: 28677722
- 8. O'Connor C et al.. 2022. Mechanisms of Feedback Regulation of Vitamin A Metabolism.. Nutrients 14(6) PMID: 35334970
