Details for: MAFA

Gene ID: 389692

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: MAFA

Ensembl ID: ENSG00000182759

Description: MAF bZIP transcription factor A

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

  • Developmental biology
    (R-HSA-1266738)
  • Regulation of beta-cell development
    (R-HSA-186712)
  • Regulation of gene expression in beta cells
    (R-HSA-210745)
  • Chromatin
    (GO:0000785)
  • Dna-binding transcription activator activity, rna polymerase ii-specific
    (GO:0001228)
  • Dna-binding transcription factor activity
    (GO:0003700)
  • Dna-binding transcription factor activity, rna polymerase ii-specific
    (GO:0000981)
  • Dna binding
    (GO:0003677)
  • Insulin secretion
    (GO:0030073)
  • Nucleus
    (GO:0005634)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Regulation of dna-templated transcription
    (GO:0006355)
  • Regulation of transcription by rna polymerase ii
    (GO:0006357)
  • Response to glucose
    (GO:0009749)
  • Rna polymerase ii cis-regulatory region sequence-specific dna binding
    (GO:0000978)
  • Sequence-specific double-stranded dna binding
    (GO:1990837)

Significant Cells

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

  • enteroendocrine cell CL0000164
    CSI 2.55
    rCSI 3.48%
    PRS 99.3
  • type B pancreatic cell CL0000169
    CSI 2.18
    rCSI 4.83%
    PRS 99.55
  • tracheobronchial serous cell CL0019001
    CSI 1
    rCSI 4.32%
    PRS 99.81

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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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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    • 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 [MAFA](/details-gene/389692) (MAF bZIP transcription factor A) is a protein-coding gene located on chromosome 8q24.3 that encodes a crucial transcription factor. As a member of the Maf family of basic-leucine zipper (bZIP) proteins, it plays a central and highly specific role in the regulation of endocrine cell function. Its primary function is as a glucose-regulated transcriptional activator for the insulin gene, making it indispensable for the proper function of pancreatic beta cells [Link](https://doi.org/10.1074/jbc.m206796200). Expression data highlights its significant role not only in [type B pancreatic cell](/details-cell/CL0000169) but also in [enteroendocrine cell](/details-cell/CL0000164), suggesting a broader involvement in metabolic homeostasis. Mutations in [MAFA](/details-gene/389692) have been linked to inherited forms of diabetes and insulinomatosis ([147630](https://omim.org/entry/147630)), underscoring its clinical importance [Link](https://doi.org/10.1073/pnas.1712262115). ## Cellular Roles and Expression Landscape The expression profile of [MAFA](/details-gene/389692) underscores its specialized function within a narrow subset of metabolically active endocrine cells. * **Overall Context:** Analysis of its expression landscape reveals its highest significance in cells responsible for hormone secretion in response to nutrient stimuli. It is a top marker in [enteroendocrine cell](/details-cell/CL0000164) (CSI: 2.55) and [type B pancreatic cell](/details-cell/CL0000169) (CSI: 2.18). This dual prominence suggests that [MAFA](/details-gene/389692) is a key transcriptional regulator not just for pancreatic insulin production but also potentially for gut-derived hormone systems involved in glucose regulation. Its function is synergistic with other key transcription factors like Beta2 and Pdx1 to drive insulin gene expression [Link](https://doi.org/10.1016/j.bbaexp.2005.05.009). The identification of [MAFA](/details-gene/389692) as the beta-cell-specific factor RIPE3b1 solidified its identity as a master regulator in this lineage [Link](https://doi.org/10.1073/pnas.102168499). Moderate significance is also noted in [tracheobronchial serous cell](/details-cell/CL0019001) (CSI: 1.00), a finding that may point toward an as-yet uncharacterized role in serous fluid secretion or cellular maintenance in the respiratory tract. ## Pathways and Molecular Function The functional annotations for [MAFA](/details-gene/389692) are highly consistent with its observed cellular expression pattern, centering on transcriptional control within the nucleus. * **Biological Processes:** [MAFA](/details-gene/389692) is deeply involved in processes critical for glucose homeostasis, including [Insulin secretion](/details-go/GO:0030073) and [Response to glucose](/details-go/GO:0009749). Its fundamental role is the [Positive regulation of transcription by rna polymerase ii](/details-go/GO:0045944), which is the mechanism through which it controls its target genes. * **Molecular Function:** At the molecular level, its functions are defined by its identity as a transcription factor. It exhibits [Dna-binding transcription factor activity, rna polymerase ii-specific](/details-go/GO:0000981) and binds to DNA via a specific mechanism inferred from its crystal structure [Link](https://doi.org/10.1021/bi301248j). It acts as a transcriptional activator, localizing to the [Nucleus](/details-go/GO:0005634) and interacting with [Chromatin](/details-go/GO:0000785) to regulate gene expression. * **Reactome Pathways:** Its involvement in developmental and regulatory pathways is explicit. It is a key component of [Regulation of gene expression in beta cells](/details-pathway/R-HSA-210745) and the broader [Regulation of beta-cell development](/details-pathway/R-HSA-186712), highlighting its role in both the maturation and functional maintenance of these critical endocrine cells. ## Research Directions The highly specific expression and critical function of [MAFA](/details-gene/389692) make it a focal point for diabetes research, while its broader endocrine roles suggest new avenues of investigation. * **Comparative Analysis and Disease Relevance:** While the provided data is aggregated, clinical research has established a direct link between [MAFA](/details-gene/389692) dysregulation and pathology. Gain-of-function missense mutations are known to cause familial insulinomatosis (a condition of excessive insulin secretion and beta-cell tumors) and, paradoxically, can also lead to diabetes mellitus later in life [Link](https://doi.org/10.1073/pnas.1712262115). This suggests a delicate balance where either over- or under-activity of [MAFA](/details-gene/389692) can disrupt glucose homeostasis, making the gene a critical node in metabolic disease. * **Testable Hypotheses:** 1. Given that gain-of-function mutations are linked to insulinomatosis, it is hypothesized that these specific mutations alter the protein's post-translational modification sites (e.g., phosphorylation or SUMOylation), leading to increased protein stability and resistance to glucose-mediated degradation, resulting in constitutive insulin gene transcription. 2. The high significance of [MAFA](/details-gene/389692) in [enteroendocrine cell](/details-cell/CL0000164) suggests it may regulate the expression of incretin hormones like Glucagon-Like Peptide-1 (GLP-1) in a nutrient-dependent manner, parallel to its role in pancreatic beta cells. Dysregulation of this intestinal [MAFA](/details-gene/389692) axis could contribute to the pathophysiology of type 2 diabetes by impairing the incretin effect. * **Proposed Experimental Approach:** To test the second hypothesis regarding its role in enteroendocrine cells, one could utilize human intestinal organoids containing a mixed population of epithelial cells, including L-cells which produce GLP-1. Using a CRISPR-Cas9 knockout strategy to ablate [MAFA](/details-gene/389692) in these organoids, researchers could then perform single-cell RNA sequencing (scRNA-seq) following stimulation with glucose and other nutrients. This would determine if the loss of [MAFA](/details-gene/389692) specifically impairs the transcriptional response and subsequent secretion of *Gcg* (the gene encoding GLP-1) and other key metabolic hormones in the L-cell population. * **Therapeutic Potential:** [MAFA](/details-gene/389692) presents a complex but compelling therapeutic target. As an intracellular transcription factor, it is challenging to target directly with small molecules. However, for type 2 diabetes, a therapeutic strategy might focus on *activation* or stabilization of the MAFA protein to enhance insulin production in remaining beta cells. This could involve developing molecules that inhibit the specific ubiquitin ligases responsible for its degradation. Conversely, for [MAFA](/details-gene/389692)-driven insulinomatosis, an *inhibitory* strategy would be required, potentially using targeted protein degraders (PROTACs) or antisense oligonucleotides designed to reduce MAFA protein levels specifically in the hyperproliferating beta cells.

Genular Protein ID: 3745245469

Symbol: MAFA_HUMAN

Name: Transcription factor MafA

UniProtKB Accession Codes:

Q8NHW3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 3 Ensembl 1 EvolutionaryTrace 1 GO 13 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TopDownProteomics 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 12368292

Title: MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene.

PubMed ID: 12368292

DOI: 10.1074/jbc.m206796200

PubMed ID: 12011435

Title: Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA.

PubMed ID: 12011435

DOI: 10.1073/pnas.102168499

PubMed ID: 16421571

Title: DNA sequence and analysis of human chromosome 8.

PubMed ID: 16421571

DOI: 10.1038/nature04406

PubMed ID: 12917329

Title: Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells.

PubMed ID: 12917329

DOI: 10.1128/mcb.23.17.6049-6062.2003

PubMed ID: 15993959

Title: Synergistic activation of the insulin gene promoter by the beta-cell enriched transcription factors MafA, Beta2, and Pdx1.

PubMed ID: 15993959

DOI: 10.1016/j.bbaexp.2005.05.009

PubMed ID: 28112733

Title: Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation.

PubMed ID: 28112733

DOI: 10.1038/nsmb.3366

PubMed ID: 23148532

Title: A novel DNA binding mechanism for maf basic region-leucine zipper factors inferred from a MafA-DNA complex structure and binding specificities.

PubMed ID: 23148532

DOI: 10.1021/bi301248j

PubMed ID: 29339498

Title: missense mutation causes familial insulinomatosis and diabetes mellitus.

PubMed ID: 29339498

DOI: 10.1073/pnas.1712262115

Sequence Information:

  • Length: 353
  • Mass: 36982
  • Checksum: 38F732D4C959AD62
  • Sequence:
    • MAAELAMGAE LPSSPLAIEY VNDFDLMKFE VKKEPPEAER FCHRLPPGSL SSTPLSTPCS 
SVPSSPSFCA PSPGTGGGGG AGGGGGSSQA GGAPGPPSGG PGAVGGTSGK PALEDLYWMS 
GYQHHLNPEA LNLTPEDAVE ALIGSGHHGA HHGAHHPAAA AAYEAFRGPG FAGGGGADDM 
GAGHHHGAHH AAHHHHAAHH HHHHHHHHGG AGHGGGAGHH VRLEERFSDD QLVSMSVREL 
NRQLRGFSKE EVIRLKQKRR TLKNRGYAQS CRFKRVQQRH ILESEKCQLQ SQVEQLKLEV 
GRLAKERDLY KEKYEKLAGR GGPGSAGGAG FPREPSPPQA GPGGAKGTAD FFL