Details for: NKX6 1

Gene ID: 4825

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: NKX6 1

Ensembl ID: ENSG00000163623

Description: NK6 homeobox 1

Cell Significance Landscape

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)
  • Regulation of gene expression in early pancreatic precursor cells
    (R-HSA-210747)
  • Animal organ morphogenesis
    (GO:0009887)
  • Cell differentiation
    (GO:0030154)
  • Cellular response to cytokine stimulus
    (GO:0071345)
  • Cellular response to peptide hormone stimulus
    (GO:0071375)
  • Central nervous system neuron differentiation
    (GO:0021953)
  • Chromatin
    (GO:0000785)
  • Chromatin binding
    (GO:0003682)
  • Dna-binding transcription factor activity, rna polymerase ii-specific
    (GO:0000981)
  • Dna-binding transcription repressor activity, rna polymerase ii-specific
    (GO:0001227)
  • Extracellular exosome
    (GO:0070062)
  • Glucose mediated signaling pathway
    (GO:0010255)
  • Negative regulation of oligodendrocyte differentiation
    (GO:0048715)
  • Negative regulation of transcription by rna polymerase ii
    (GO:0000122)
  • Nucleus
    (GO:0005634)
  • Oligodendrocyte differentiation
    (GO:0048709)
  • Pancreas development
    (GO:0031016)
  • Pancreatic a cell differentiation
    (GO:0003310)
  • Positive regulation of dna-binding transcription factor activity
    (GO:0051091)
  • Positive regulation of insulin secretion
    (GO:0032024)
  • Positive regulation of neuron differentiation
    (GO:0045666)
  • Positive regulation of oligodendrocyte differentiation
    (GO:0048714)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Positive regulation of type b pancreatic cell development
    (GO:2000078)
  • Regulation of axon extension
    (GO:0030516)
  • Regulation of neuron migration
    (GO:2001222)
  • Regulation of transcription by rna polymerase ii
    (GO:0006357)
  • Response to nicotine
    (GO:0035094)
  • Response to xenobiotic stimulus
    (GO:0009410)
  • Rna polymerase ii cis-regulatory region sequence-specific dna binding
    (GO:0000978)
  • Smoothened signaling pathway
    (GO:0007224)
  • Transcription by rna polymerase ii
    (GO:0006366)
  • Type b pancreatic cell maturation
    (GO:0072560)
  • Type b pancreatic cell proliferation
    (GO:0044342)

Significant Cells

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

  • type B pancreatic cell CL0000169
    CSI 7.7
    rCSI 17.04%
    PRS 99.53
  • pancreatic D cell CL0000173
    CSI 6.2
    rCSI 6.09%
    PRS 99.73

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.

Comma-separated if multiple.
Comma-separated if multiple.
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 [NKX6 1](/details-gene/4825) (NK6 homeobox 1) is a protein-coding gene located on chromosome 4 that encodes a homeobox-containing transcription factor. This protein is a critical regulator of cellular differentiation and development, particularly within the pancreas and the central nervous system. As described in early characterization studies, it is a key pancreatic islet homeobox gene ([Link](https://pubmed.ncbi.nlm.nih.gov/9119408/)). Data from the **Overall** context confirms its role as a highly specific and significant marker for pancreatic endocrine cells, showing the highest significance in [type B pancreatic cell](/details-cell/CL0000169) (CSI: 7.70) and [pancreatic D cell](/details-cell/CL0000173) (CSI: 6.20). Its function is primarily executed within the [nucleus](/details-cell/GO:0005634) where it binds to [chromatin](/details-cell/GO:0000785) and regulates the transcription of target genes essential for cell fate determination and maturation. The clinical relevance of [NKX6 1](/details-gene/4825) is highlighted by its association with developmental disorders related to pancreatic function ([OMIM:602563](https://omim.org/entry/602563)). ## Cellular Roles and Expression Landscape The expression profile of [NKX6 1](/details-gene/4825) demonstrates a highly specialized role in endocrine cell identity within the pancreas. **Overall**, the gene exhibits its most significant expression in [type B pancreatic cell](/details-cell/CL0000169) and [pancreatic D cell](/details-cell/CL0000173), underscoring its essential function in the islets of Langerhans. This restricted expression pattern suggests it is a master regulator responsible for establishing and maintaining the identity and function of these hormone-secreting cells. While the expression data strongly points to a pancreatic role, functional annotations also indicate its involvement in neurogenesis, including [central nervous system neuron differentiation](/details-cell/GO:0021953) and the [negative regulation of oligodendrocyte differentiation](/details-cell/GO:0048715). This suggests that [NKX6 1](/details-gene/4825) may play a transient but critical role during the development of specific neural lineages, a role that may not be captured in broad expression atlases of mature tissues. Its primary function appears to be as a lineage-defining transcription factor, with its expression tightly controlled to ensure proper cell fate decisions during organogenesis. ## Pathways and Molecular Function Functionally, [NKX6 1](/details-gene/4825) operates as a [DNA-binding transcription factor activity, rna polymerase ii-specific](/details-cell/GO:0000981) that binds to cis-regulatory regions of DNA ([GO:0000978](https://www.ebi.ac.uk/QuickGO/term/GO:0000978)) to modulate gene expression. It can act as both an activator ([positive regulation of transcription by rna polymerase ii](/details-cell/GO:0045944)) and a repressor ([DNA-binding transcription repressor activity, rna polymerase ii-specific](/details-cell/GO:0001227)) of transcription, indicating a complex, context-dependent regulatory role. This dual function is central to its involvement in key developmental pathways. Its high significance in pancreatic beta cells is explained by its direct participation in the [Regulation of beta-cell development](/details-pathway/R-HSA-186712) and [Regulation of gene expression in beta cells](/details-pathway/R-HSA-210745). Specifically, it is involved in processes such as [positive regulation of type b pancreatic cell development](/details-cell/GO:2000078), [type b pancreatic cell maturation](/details-cell/GO:0072560), and the [positive regulation of insulin secretion](/details-cell/GO:0032024). Beyond the pancreas, its role in broader [Developmental biology](/details-pathway/R-HSA-1266738) is supported by its involvement in [animal organ morphogenesis](/details-cell/GO:0009887) and the differentiation of multiple cell types. ## Research Directions Given the critical and highly specific role of [NKX6 1](/details-gene/4825) in pancreatic beta-cell identity, research should focus on its potential dysregulation in metabolic diseases like diabetes mellitus. Alterations in its expression or function could plausibly lead to beta-cell failure, de-differentiation, or a reduced capacity for regeneration. **Proposed Hypotheses:** 1. *Loss of [NKX6 1](/details-gene/4825) in adult pancreatic beta-cells under conditions of metabolic stress (e.g., hyperglycemia, hyperlipidemia) is a key event that triggers beta-cell de-differentiation and a subsequent loss of glucose-stimulated insulin secretion, contributing to the pathophysiology of Type 2 diabetes.* 2. *[NKX6 1](/details-gene/4825) orchestrates a specific chromatin accessibility landscape required for beta-cell function, and its loss leads to the ectopic expression of genes characteristic of other endocrine or progenitor cell types, thereby compromising cellular identity.* **Experimental Approach:** To test the first hypothesis, a conditional knockout mouse model could be employed. Specifically, using a tamoxifen-inducible Cre-lox system (e.g., Pdx1-CreERT) to delete [NKX6 1](/details-gene/4825) exclusively in the pancreatic beta-cells of adult mice would allow for a precise investigation of its role in maintaining the mature cell state. These mice could then be subjected to a high-fat diet to induce metabolic stress. The impact of [NKX6 1](/details-gene/4825) deletion would be assessed by monitoring glucose tolerance, performing in vivo and ex vivo glucose-stimulated insulin secretion assays on isolated islets, and conducting single-cell RNA-sequencing (scRNA-seq) on islets to track changes in cell identity and gene expression programs. **Therapeutic Potential:** [NKX6 1](/details-gene/4825) is not a conventional therapeutic target for small molecule inhibition or activation due to its nature as an intracellular transcription factor. However, its profound influence on beta-cell fate makes it a prime target for regenerative medicine and cell therapy approaches. Its potential lies in its use as a key factor to drive the directed differentiation of pluripotent stem cells (PSCs) into functional, insulin-producing [type B pancreatic cell](/details-cell/CL0000169)s. Optimizing the timing and level of [NKX6 1](/details-gene/4825) expression during in vitro differentiation protocols could significantly improve the yield and functionality of stem cell-derived beta-cells for transplantation into patients with Type 1 diabetes.

Genular Protein ID: 3627409208

Symbol: NKX61_HUMAN

Name: Homeobox protein Nkx-6.1

UniProtKB Accession Codes:

P78426

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 4 Ensembl 1 ExpressionAtlas 1 GO 33 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 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 Pumba 1 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9119408

Title: Isolation, characterization, and chromosomal mapping of the human Nkx6.1 gene (NKX6A), a new pancreatic islet homeobox gene.

PubMed ID: 9119408

DOI: 10.1006/geno.1996.4568

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 24129315

Title: Immunoaffinity enrichment and mass spectrometry analysis of protein methylation.

PubMed ID: 24129315

DOI: 10.1074/mcp.o113.027870

Sequence Information:

  • Length: 367
  • Mass: 37849
  • Checksum: 5C78F06C3CAE6486
  • Sequence:
    • MLAVGAMEGT RQSAFLLSSP PLAALHSMAE MKTPLYPAAY PPLPAGPPSS SSSSSSSSSP 
SPPLGTHNPG GLKPPATGGL SSLGSPPQQL SAATPHGIND ILSRPSMPVA SGAALPSASP 
SGSSSSSSSS ASASSASAAA AAAAAAAAAA SSPAGLLAGL PRFSSLSPPP PPPGLYFSPS 
AAAVAAVGRY PKPLAELPGR TPIFWPGVMQ SPPWRDARLA CTPHQGSILL DKDGKRKHTR 
PTFSGQQIFA LEKTFEQTKY LAGPERARLA YSLGMTESQV KVWFQNRRTK WRKKHAAEMA 
TAKKKQDSET ERLKGASENE EEDDDYNKPL DPNSDDEKIT QLLKKHKSSS GGGGGLLLHA 
SEPESSS