Details for: REG3A

Gene ID: 5068

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: REG3A

Ensembl ID: ENSG00000172016

Description: regenerating family member 3 alpha

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • paneth cell CL0000510
    CSI 19.69
    rCSI 29.07%
    PRS 99.05
  • pancreatic acinar cell CL0002064
    CSI 9.35
    rCSI 12.42%
    PRS 98.36
  • small intestine goblet cell CL1000495
    CSI 4.63
    rCSI 10.15%
    PRS 98.38
  • goblet cell CL0000160
    CSI 4.54
    rCSI 4.29%
    PRS 97.35
  • colonocyte CL1000347
    CSI 3.58
    rCSI 5.13%
    PRS 97.39
  • intestine goblet cell CL0019031
    CSI 3.52
    rCSI 3.12%
    PRS 97.33
  • type L enteroendocrine cell CL0002279
    CSI 3.36
    rCSI 6.31%
    PRS 97.97
  • mucous neck cell CL0000651
    CSI 3.19
    rCSI 4.6%
    PRS 98.3
  • paneth cell of epithelium of small intestine CL1000343
    CSI 2.96
    rCSI 8.29%
    PRS 98.63
  • glial cell CL0000125
    CSI 2.73
    rCSI 10.38%
    PRS 95.23
  • plasma cell CL0000786
    CSI 2.62
    rCSI 3.43%
    PRS 98.29
  • enteroendocrine cell CL0000164
    CSI 2.18
    rCSI 2.98%
    PRS 96.94
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.44
    rCSI 3.87%
    PRS 98.53
  • pancreatic ductal cell CL0002079
    CSI 1.44
    rCSI 2.79%
    PRS 98.02
  • transit amplifying cell of small intestine CL0009012
    CSI 1.13
    rCSI 4.95%
    PRS 98.69
  • type EC enteroendocrine cell CL0000577
    CSI 1.02
    rCSI 3.61%
    PRS 97.85

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [REG3A](/details-gene/5068) (Regenerating Family Member 3 Alpha) is a protein-coding gene located on chromosome 2p12. It encodes a secreted C-type lectin that functions as a key component of the innate immune system, particularly in mucosal tissues. As an antimicrobial peptide, [REG3A](/details-gene/5068) exhibits bactericidal activity, primarily against Gram-positive bacteria, by binding to peptidoglycan and forming pores in the bacterial membrane ([Link](https://doi.org/10.1073/pnas.0909449107), [Link](https://doi.org/10.1038/nature12729)). **Overall**, its expression is highly specific and abundant in secretory epithelial cells of the gastrointestinal tract and pancreas, most notably [paneth cell](/details-cell/CL0000510)s and [pancreatic acinar cell](/details-cell/CL0002064)s. Beyond its antimicrobial function, [REG3A](/details-gene/5068) is implicated in tissue regeneration, wound healing, and the regulation of cellular proliferation and differentiation, with dysregulation associated with pancreatitis ([OMIM](/entry/167805)) and certain cancers ([Link](https://pubmed.ncbi.nlm.nih.gov/1325291/)). ## Cellular Roles and Expression Landscape The expression profile of [REG3A](/details-gene/5068) highlights its specialized role in epithelial defense and secretion within the digestive system. **Overall**, the gene shows exceptionally high significance in [paneth cell](/details-cell/CL0000510)s (CSI: 19.69), which are known to secrete antimicrobial peptides into the intestinal crypts, and in [pancreatic acinar cell](/details-cell/CL0002064)s (CSI: 9.35), the primary producers of digestive enzymes. This pattern is consistent with its discovery as a pancreatitis-associated protein ([Link](https://doi.org/10.1172/jci116115)). Significant expression is also observed in other secretory cell types along the gastrointestinal tract, including [small intestine goblet cell](/details-cell/CL1000495)s, [colonocyte](/details-cell/CL1000347)s, and [enteroendocrine cell](/details-cell/CL0000164)s. This collective expression profile strongly suggests that [REG3A](/details-gene/5068) is a central effector molecule in maintaining mucosal barrier integrity and shaping the gut microbiome. Its expression in response to symbiotic bacteria further supports this role as a mediator of host-microbe interactions ([Link](https://doi.org/10.1126/science.1127119)). The presence in intestinal stem and transit-amplifying cells suggests a potential role in epithelial renewal and repair following injury. ## Pathways and Molecular Function Functionally, [REG3A](/details-gene/5068) is deeply integrated into the [Innate immune system](/content/detail/R-HSA-168249), as categorized by Reactome. Its primary molecular function is carbohydrate binding ([GO:0030246](https://www.ebi.ac.uk/QuickGO/term/GO:0030246)), specifically peptidoglycan binding ([GO:0042834](https://www.ebi.ac.uk/QuickGO/term/GO:0042834)), which is essential for its role in the [Antimicrobial humoral immune response mediated by antimicrobial peptide](/content/detail/GO:0061844) ([Link](https://doi.org/10.1042/bj20090005)). This activity is a core part of the broader [Antimicrobial peptides](/content/detail/R-HSA-6803157) pathway. In addition to host defense, [REG3A](/details-gene/5068) participates in tissue homeostasis and response to injury. It is involved in the [Acute-phase response](/content/detail/GO:0006953) and [Response to wounding](/content/detail/GO:0009611), with evidence showing it promotes [Positive regulation of wound healing](/content/detail/GO:0090303) and modulates keratinocyte proliferation and differentiation ([GO:0010838](https://www.ebi.ac.uk/QuickGO/term/GO:0010838), [GO:0045617](https://www.ebi.ac.uk/QuickGO/term/GO:0045617)) ([Link](https://doi.org/10.1016/j.immuni.2012.04.010)). Recent studies indicate it can also promote acinar to ductal metaplasia in the pancreas by binding the receptor EXTL3 and activating MAPK signaling, linking its regenerative function to pathological processes ([Link](https://doi.org/10.1038/s42003-021-02193-z)). ## Research Directions The dual role of [REG3A](/details-gene/5068) in both protective immunity/regeneration and pathological cell state transitions presents compelling avenues for future research. Its high specificity for secretory epithelial cells in the gut and pancreas makes it a molecule of significant interest for both inflammatory and neoplastic diseases of these organs. **Proposed Hypotheses:** 1. Given its established role in skin wound healing and high expression in the intestinal epithelium, [REG3A](/details-gene/5068) functions as a critical enteric growth factor that promotes mucosal healing and barrier restoration following damage, such as in colitis. Its deficiency may therefore exacerbate inflammatory bowel disease (IBD) pathology by impairing epithelial repair and antimicrobial defense. 2. Based on its association with pancreatitis and its recently identified role in promoting acinar-to-ductal metaplasia ([Link](https://doi.org/10.1038/s42003-021-02193-z)), chronic inflammatory signaling that drives sustained high-level expression of [REG3A](/details-gene/5068) in the pancreas is a key initiating event that drives the development of pre-neoplastic lesions, contributing to the progression towards pancreatic ductal adenocarcinoma. **Experimental Approach:** To test the first hypothesis regarding its role in IBD, an ideal approach would involve using a dextran sulfate sodium (DSS)-induced colitis model in mice. A conditional knockout of *Reg3a* specifically in intestinal epithelial cells could be generated. These mice, alongside wild-type controls, would be subjected to DSS treatment. The severity of colitis would be assessed by monitoring weight loss, stool consistency, and colon length. Histological analysis would evaluate tissue damage and inflammatory infiltrate, while intestinal permeability could be measured *in vivo* using FITC-dextran. Furthermore, 16S rRNA gene sequencing of fecal samples would determine if the absence of *Reg3a* leads to dysbiosis that contributes to disease severity. **Therapeutic Potential:** The therapeutic potential of [REG3A](/details-gene/5068) is highly context-dependent. As a secreted protein, it is an accessible drug target. For conditions characterized by epithelial injury and microbial imbalance, such as IBD or infectious enteritis, topical or systemic administration of recombinant [REG3A](/details-gene/5068) could represent a novel **activation** strategy to enhance mucosal healing and bolster innate defense. Conversely, in diseases driven by [REG3A](/details-gene/5068)-mediated metaplasia and proliferation, such as in early pancreatitis or pancreatic cancer, a therapeutic **inhibition** strategy using neutralizing monoclonal antibodies or small molecule inhibitors of its receptor, EXTL3, would be a promising approach to halt disease progression.

Genular Protein ID: 2169022170

Symbol: REG3A_HUMAN

Name: Regenerating islet-derived protein 3-alpha

UniProtKB Accession Codes:

Q06141

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 4 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 6 EMDB 1 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 22 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PIR 1 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 3 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 UniLectin 1 VEuPathDB 1 eggNOG 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7679928

Title: Cloning and tissue-specific expression of cDNAs for the human and mouse homologues of rat pancreatitis-associated protein (PAP).

PubMed ID: 7679928

DOI: 10.1016/0167-4781(93)90290-t

PubMed ID: 1469087

Title: Human pancreatitis-associated protein. Messenger RNA cloning and expression in pancreatic diseases.

PubMed ID: 1469087

DOI: 10.1172/jci116115

PubMed ID: 1325291

Title: A novel gene (HIP) activated in human primary liver cancer.

PubMed ID: 1325291

PubMed ID: 8188210

Title: Molecular cloning, genomic organization, and chromosomal localization of the human pancreatitis-associated protein (PAP) gene.

PubMed ID: 8188210

DOI: 10.1006/geno.1994.1019

PubMed ID: 8076648

Title: Structural organization and chromosomal localization of a human gene (HIP/PAP) encoding a C-type lectin overexpressed in primary liver cancer.

PubMed ID: 8076648

DOI: 10.1111/j.1432-1033.1994.tb19991.x

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 19254208

Title: Proteolytic activation of human pancreatitis-associated protein is required for peptidoglycan binding and bacterial aggregation.

PubMed ID: 19254208

DOI: 10.1042/bj20090005

PubMed ID: 16931762

Title: Symbiotic bacteria direct expression of an intestinal bactericidal lectin.

PubMed ID: 16931762

DOI: 10.1126/science.1127119

PubMed ID: 19158046

Title: Discovery of a human peptide sequence signaling islet neogenesis.

PubMed ID: 19158046

DOI: 10.4158/ep.14.9.1075

PubMed ID: 22727489

Title: The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury.

PubMed ID: 22727489

DOI: 10.1016/j.immuni.2012.04.010

PubMed ID: 27830702

Title: Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes.

PubMed ID: 27830702

DOI: 10.1038/ncomms13393

PubMed ID: 34099862

Title: REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway.

PubMed ID: 34099862

DOI: 10.1038/s42003-021-02193-z

PubMed ID: 20382864

Title: Molecular basis for peptidoglycan recognition by a bactericidal lectin.

PubMed ID: 20382864

DOI: 10.1073/pnas.0909449107

PubMed ID: 24256734

Title: Antibacterial membrane attack by a pore-forming intestinal C-type lectin.

PubMed ID: 24256734

DOI: 10.1038/nature12729

Sequence Information:

  • Length: 175
  • Mass: 19395
  • Checksum: C51149FAC22EB68C
  • Sequence:
    • MLPPMALPSV SWMLLSCLML LSQVQGEEPQ RELPSARIRC PKGSKAYGSH CYALFLSPKS 
WTDADLACQK RPSGNLVSVL SGAEGSFVSS LVKSIGNSYS YVWIGLHDPT QGTEPNGEGW 
EWSSSDVMNY FAWERNPSTI SSPGHCASLS RSTAFLRWKD YNCNVRLPYV CKFTD