Details for: N6AMT1

Gene ID: 29104

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: N6AMT1

Ensembl ID: ENSG00000156239

Description: N-6 adenine-specific DNA methyltransferase 1

Cell Significance Landscape

Associated with

Significant Cells

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

  • multi-ciliated epithelial cell CL0005012
    CSI 4.07
    rCSI 4.06%
    PRS 98.75
  • neural crest cell CL0011012
    CSI 4.04
    rCSI 3.19%
    PRS 99.38
  • ciliated epithelial cell CL0000067
    CSI 3.46
    rCSI 3.04%
    PRS 98.33
  • ciliated cell CL0000064
    CSI 3.15
    rCSI 5.11%
    PRS 98.2
  • lung ciliated cell CL1000271
    CSI 2.9
    rCSI 3.35%
    PRS 98.81
  • retinal bipolar neuron CL0000748
    CSI 2.88
    rCSI 5.39%
    PRS 98.26
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 1.94
    rCSI 4.42%
    PRS 98.23

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 [N6AMT1](/details-gene/29104) (N-6 Adenine-Specific DNA Methyltransferase 1) is a protein-coding gene located on chromosome 21q21.3 that encodes a methyltransferase with multifaceted roles. While its name suggests a primary function in DNA methylation, substantial evidence points to its critical activity as a protein methyltransferase involved in translation termination by methylating the release factor eRF1 ([Link](https://pubmed.ncbi.nlm.nih.gov/18539146/)). The gene is also implicated in the metabolic processing of toxins, particularly arsenic biomethylation ([Link](https://doi.org/10.1289/ehp.1002733)). **Overall**, expression data reveals that [N6AMT1](/details-gene/29104) is a highly significant gene in various types of ciliated epithelial cells and certain neuronal populations, suggesting a specialized role in these cellular contexts. ## Cellular Roles and Expression Landscape The expression profile of [N6AMT1](/details-gene/29104) indicates a prominent and specialized function in cells characterized by cilia. **Overall**, it demonstrates high significance in `[multi-ciliated epithelial cell](/details-cell/CL0005012)` (CSI: 4.07), `[ciliated epithelial cell](/details-cell/CL0000067)` (CSI: 3.46), `[ciliated cell](/details-cell/CL0000064)` (CSI: 3.15), and more specifically in `[lung ciliated cell](/details-cell/CL1000271)` (CSI: 2.90) and `[ciliated columnar cell of tracheobronchial tree](/details-cell/CL0002145)` (CSI: 1.94). This consistent high ranking across multiple ciliated cell types strongly suggests its involvement in the development, maintenance, or function of ciliary structures. Beyond epithelial tissues, [N6AMT1](/details-gene/29104) also shows high significance in `[neural crest cell](/details-cell/CL0011012)` (CSI: 4.04) and `[retinal bipolar neuron](/details-cell/CL0000748)` (CSI: 2.88). This pattern suggests that its functions may extend to developmental processes and specialized roles within the nervous system, potentially related to epigenetic regulation or protein synthesis fidelity during differentiation and neuronal function. ## Pathways and Molecular Function [N6AMT1](/details-gene/29104) functions as an S-adenosylmethionine-dependent methyltransferase ([GO:0008757](https://www.ebi.ac.uk/QuickGO/term/GO:0008757)), participating in fundamental biological processes. A key annotated function is its role in protein metabolism, specifically as a protein-glutamine N-methyltransferase ([GO:0036009](https://www.ebi.ac.uk/QuickGO/term/GO:0036009)) within the `[Eukaryotic translation termination](/details-pathway/R-HSA-72764)` pathway ([R-HSA-72764](https://reactome.org/content/detail/R-HSA-72764)). Studies have demonstrated that it methylates the eukaryotic release factor 1 (eRF1), a crucial step for efficient protein synthesis termination, and its deficiency is embryonically lethal in mice ([Link](https://doi.org/10.1128/mcb.00218-10)). The gene is also annotated with roles in the `[Toxin metabolic process](/details-pathway/GO:0009404)` ([GO:0009404](https://www.ebi.ac.uk/QuickGO/term/GO:0009404)), particularly through its `[Arsenite methyltransferase activity](/details-pathway/GO:0030791)` ([GO:0030791](https://www.ebi.ac.uk/QuickGO/term/GO:0030791)). This activity is central to arsenic detoxification pathways ([Link](https://doi.org/10.1289/ehp.1002733)). While named for DNA methylation ([GO:0009007](https://www.ebi.ac.uk/QuickGO/term/GO:0009007)), its role in modifying mammalian genomic DNA remains a subject of investigation, with some reports suggesting it may not act on DNA directly *in vitro* ([Link](https://doi.org/10.1038/s41421-019-0119-5)), while others link N6-methyladenine modification to conditions like glioblastoma ([Link](https://doi.org/10.1016/j.cell.2018.10.006)). ## Research Directions The distinct expression pattern and multifaceted functions of [N6AMT1](/details-gene/29104) suggest several avenues for future research. The strong enrichment in ciliated cells, coupled with its fundamental role in translation termination, points toward a specialized function in maintaining the complex ciliary proteome. ### Proposed Hypotheses: 1. **Hypothesis 1:** [N6AMT1](/details-gene/29104)-mediated methylation of eRF1 is critical for the high-fidelity and efficient synthesis of the extensive repertoire of proteins required for ciliogenesis and the maintenance of ciliary structure and function. 2. **Hypothesis 2:** In the context of developmental biology, the high significance of [N6AMT1](/details-gene/29104) in `[neural crest cell](/details-cell/CL0011012)` suggests it acts as an epigenetic regulator, possibly through DNA or histone methylation ([GO:0045814](https://www.ebi.ac.uk/QuickGO/term/GO:0045814)), to control gene expression programs essential for neural crest lineage specification. ### Experimental Approach: To test Hypothesis 1, one could utilize an *in vitro* air-liquid interface (ALI) culture system with primary human bronchial epithelial cells, which differentiate to form a ciliated epithelium. Following siRNA- or CRISPR-Cas9-mediated knockdown or knockout of [N6AMT1](/details-gene/29104), the effects on ciliogenesis could be quantitatively assessed using immunofluorescence staining for ciliary markers (e.g., acetylated tubulin) and high-resolution microscopy. Furthermore, ciliary beat frequency could be measured via high-speed video microscopy to determine functional consequences. Proteomic analysis of these cells could then identify specific ciliary proteins whose synthesis is dysregulated. ### Therapeutic Potential: Given its fundamental role in translation, systemic targeting of [N6AMT1](/details-gene/29104) would likely result in significant toxicity. However, its specific functions offer niche therapeutic possibilities. Its involvement in arsenic metabolism suggests it could be a target for modulating individual susceptibility to arsenic toxicity. Moreover, its reported link to N6-methyladenine DNA modification in glioblastoma ([Link](https://doi.org/10.1016/j.cell.2018.10.006)) suggests that inhibitors of [N6AMT1](/details-gene/29104) could be explored as a targeted therapy for specific cancer subtypes where this epigenetic mark is oncogenic. This would represent an inhibitory strategy aimed at reversing aberrant methylation patterns.

Genular Protein ID: 2767319349

Symbol: N6MT1_HUMAN

Name: Methylarsonite methyltransferase N6AMT1

UniProtKB Accession Codes:

Q9Y5N5 B2RA97 Q96F73

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 2 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ChEBI 31 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 12 Ensembl 3 GO 19 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 8 PDBsum 8 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 2 RefSeq 2 Rhea 9 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 2 VEuPathDB 1 eggNOG 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 10830953

Title: The DNA sequence of human chromosome 21.

PubMed ID: 10830953

DOI: 10.1038/35012518

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: 18539146

Title: HemK2 protein, encoded on human chromosome 21, methylates translation termination factor eRF1.

PubMed ID: 18539146

DOI: 10.1016/j.febslet.2008.05.045

PubMed ID: 20606008

Title: Deficiency in a glutamine-specific methyltransferase for release factor causes mouse embryonic lethality.

PubMed ID: 20606008

DOI: 10.1128/mcb.00218-10

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21193388

Title: Involvement of N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) in arsenic biomethylation and its role in arsenic-induced toxicity.

PubMed ID: 21193388

DOI: 10.1289/ehp.1002733

PubMed ID: 25851604

Title: The human 18S rRNA base methyltransferases DIMT1L and WBSCR22-TRMT112 but not rRNA modification are required for ribosome biogenesis.

PubMed ID: 25851604

DOI: 10.1091/mbc.e15-02-0073

PubMed ID: 25997655

Title: Interactive effects of N6AMT1 and As3MT in arsenic biomethylation.

PubMed ID: 25997655

DOI: 10.1093/toxsci/kfv101

PubMed ID: 30392959

Title: N6-methyladenine DNA modification in glioblastoma.

PubMed ID: 30392959

DOI: 10.1016/j.cell.2018.10.006

PubMed ID: 30017583

Title: N6-methyladenine DNA modification in the human genome.

PubMed ID: 30017583

DOI: 10.1016/j.molcel.2018.06.015

PubMed ID: 31466382

Title: The Common Partner of Several Methyltransferases TRMT112 Regulates the Expression of N6AMT1 Isoforms in Mammalian Cells.

PubMed ID: 31466382

DOI: 10.3390/biom9090422

PubMed ID: 31632689

Title: Human HemK2/KMT9/N6AMT1 is an active protein methyltransferase, but does not act on DNA in vitro, in the presence of Trm112.

PubMed ID: 31632689

DOI: 10.1038/s41421-019-0119-5

PubMed ID: 32203414

Title: The origin of genomic N6-methyl-deoxyadenosine in mammalian cells.

PubMed ID: 32203414

DOI: 10.1038/s41589-020-0504-2

PubMed ID: 34948388

Title: Human TRMT112-Methyltransferase Network Consists of Seven Partners Interacting with a Common Co-Factor.

PubMed ID: 34948388

DOI: 10.3390/ijms222413593

PubMed ID: 31636962

Title: Structural insight into human N6amt1-Trm112 complex functioning as a protein methyltransferase.

PubMed ID: 31636962

DOI: 10.1038/s41421-019-0121-y

PubMed ID: 31061526

Title: KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells.

PubMed ID: 31061526

DOI: 10.1038/s41594-019-0219-9

PubMed ID: 32969463

Title: Structural insight into HEMK2-TRMT112-mediated glutamine methylation.

PubMed ID: 32969463

DOI: 10.1042/bcj20200594

Sequence Information:

  • Length: 214
  • Mass: 22957
  • Checksum: 65512C91DC85ADDB
  • Sequence:
    • MAGENFATPF HGHVGRGAFS DVYEPAEDTF LLLDALEAAA AELAGVEICL EVGSGSGVVS 
AFLASMIGPQ ALYMCTDINP EAAACTLETA RCNKVHIQPV ITDLVKGLLP RLTEKVDLLV 
FNPPYVVTPP QEVGSHGIEA AWAGGRNGRE VMDRFFPLVP DLLSPRGLFY LVTIKENNPE 
EILKIMKTKG LQGTTALSRQ AGQETLSVLK FTKS