Details for: SETD9

Gene ID: 133383

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: SETD9

Ensembl ID: ENSG00000155542

Description: SET domain containing 9

Cell Significance Landscape

Associated with

Significant Cells

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

  • regulatory T cell CL0000815
    CSI 10.07
    rCSI 11.67%
    PRS 95.29
  • helper T cell CL0000912
    CSI 9.74
    rCSI 13.77%
    PRS 96.19
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 6.86
    rCSI 8.31%
    PRS 90.28
  • basal cell of epidermis CL0002187
    CSI 5.74
    rCSI 10.17%
    PRS 86.75
  • suprabasal keratinocyte CL4033013
    CSI 5.73
    rCSI 9.35%
    PRS 88.53
  • hematopoietic stem cell CL0000037
    CSI 5.53
    rCSI 3.68%
    PRS 99.35
  • chondrocyte CL0000138
    CSI 5.48
    rCSI 8.71%
    PRS 97.74
  • erythrocyte CL0000232
    CSI 5.38
    rCSI 12.21%
    PRS 98.04
  • vascular associated smooth muscle cell CL0000359
    CSI 4.5
    rCSI 14.59%
    PRS 99.05
  • melanocyte of skin CL1000458
    CSI 4.5
    rCSI 6.13%
    PRS 87.94
  • innate lymphoid cell CL0001065
    CSI 4.19
    rCSI 8.66%
    PRS 95.83
  • neural crest cell CL0011012
    CSI 4.16
    rCSI 3.29%
    PRS 98.45
  • GABAergic neuron CL0000617
    CSI 3.6
    rCSI 12.05%
    PRS 94.3
  • colon epithelial cell CL0011108
    CSI 3.46
    rCSI 3.63%
    PRS 98.84
  • club cell CL0000158
    CSI 3.34
    rCSI 4.9%
    PRS 98.96
  • neural progenitor cell CL0011020
    CSI 3.24
    rCSI 14.24%
    PRS 94.74
  • stem cell CL0000034
    CSI 3.22
    rCSI 3.11%
    PRS 98.79
  • common myeloid progenitor CL0000049
    CSI 3.22
    rCSI 2.6%
    PRS 99.56
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 3.17
    rCSI 2.87%
    PRS 99.1
  • cytotoxic T cell CL0000910
    CSI 2.15
    rCSI 12.3%
    PRS 96.71

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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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 [SETD9](/details-gene/133383) (SET domain containing 9) is a protein-coding gene located on chromosome 5q11.2 [[Link](https://doi.org/10.1038/nature02919)]. It encodes a lysine n-methyltransferase, an enzyme that plays a crucial role in epigenetic regulation through the methylation of both histone and non-histone proteins. Functionally, [SETD9](/details-gene/133383) is integral to the regulation of [gene expression (transcription)](https://reactome.org/content/detail/R-HSA-74160) and is specifically implicated in modulating the activity of the tumor suppressor p53. Expression data from the **Overall** context indicates its highest significance in immune cells, particularly [regulatory T cell](/details-cell/CL0000815) and [helper T cell](/details-cell/CL0000912), suggesting a key role in adaptive immunity. Its notable expression in other diverse cell types, including epidermal cells and [hematopoietic stem cell](/details-cell/CL0000037), points to a broader function in cellular homeostasis, proliferation, and stress response across multiple tissues. The characterization of this gene has been supported by large-scale cDNA projects [[Link](https://doi.org/10.1101/gr.2596504)]. ## Cellular Roles and Expression Landscape The expression profile of [SETD9](/details-gene/133383) highlights its importance in a wide range of cell types, with a particularly strong signature in the adaptive immune system. **Overall**, the gene shows its highest significance in lymphocyte populations, including [regulatory T cell](/details-cell/CL0000815) (CSI: 10.07), [helper T cell](/details-cell/CL0000912) (CSI: 9.74), and [CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203) (CSI: 6.86). This suggests a fundamental role in T cell development, activation, or function. Beyond the immune system, [SETD9](/details-gene/133383) is also highly significant in tissues undergoing regular turnover and differentiation. It is prominently expressed in [basal cell of epidermis](/details-cell/CL0002187) (CSI: 5.74) and [suprabasal keratinocyte](/details-cell/CL4033013) (CSI: 5.73), indicating a potential role in skin barrier maintenance and response to environmental stress. Its significance in [hematopoietic stem cell](/details-cell/CL0000037) (CSI: 5.53) further implies a function in the regulation of self-renewal and lineage commitment. The broad, yet specific, pattern of high expression across diverse cell lineages—from [chondrocyte](/details-cell/CL0000138) to [GABAergic neuron](/details-cell/CL0000617)—is consistent with its role as a fundamental regulator of transcription and cellular signaling. ## Pathways and Molecular Function The primary molecular function of [SETD9](/details-gene/133383) is its [lysine n-methyltransferase activity](/details-go/GO:0016278), through which it participates in the biological process of [methylation](/details-go/GO:0032259). This enzymatic activity is central to its role in regulating gene expression. According to Reactome pathway analysis, [SETD9](/details-gene/133383) is a key component of the [Generic transcription pathway](https://reactome.org/content/detail/R-HSA-212436) and [Rna polymerase ii transcription](https://reactome.org/content/detail/R-HSA-73857). A particularly well-defined role for [SETD9](/details-gene/133383) is in the p53 signaling network. It is directly involved in the [Regulation of tp53 activity through methylation](https://reactome.org/content/detail/R-HSA-6804760), which in turn influences the broader [Transcriptional regulation by tp53](https://reactome.org/content/detail/R-HSA-3700989) pathway. By methylating p53, [SETD9](/details-gene/133383) can stabilize it and modulate its transcriptional activity, impacting cellular responses to DNA damage, cell cycle arrest, and apoptosis. This function likely connects its high expression in T cells (where p53 regulates activation-induced cell death) and keratinocytes (where p53 is critical for responding to UV-induced damage). The protein is localized to both the [nucleoplasm](/details-go/GO:0005654) and [mitochondrion](/details-go/GO:0005739), suggesting it may have distinct regulatory roles in both compartments. ## Research Directions The widespread yet cell-type-specific significance of [SETD9](/details-gene/133383), combined with its role as an epigenetic modifier of the critical p53 pathway, opens several avenues for future investigation. **Proposed Hypotheses:** 1. Given its high significance in [regulatory T cell](/details-cell/CL0000815) and its function in transcriptional control, the methyltransferase activity of [SETD9](/details-gene/133383) may be essential for establishing or maintaining the suppressive lineage identity of Tregs, potentially through direct methylation of the master transcription factor FOXP3 or associated histone marks at key gene loci. 2. In epidermal cells like [basal cell of epidermis](/details-cell/CL0002187), [SETD9](/details-gene/133383) likely acts as a critical modulator of the cellular response to genotoxic stress. It may fine-tune p53 activation following UV radiation exposure, thereby controlling the balance between DNA repair, apoptosis, and cellular senescence to prevent malignant transformation. **Experimental Approach:** To test the first hypothesis regarding the role of [SETD9](/details-gene/133383) in Treg function, a conditional knockout mouse model using a *Foxp3-Cre* driver could be generated. Tregs isolated from these [SETD9](/details-gene/133383)-deficient mice would be functionally assessed for their suppressive capacity in *in vitro* co-culture assays with conventional T cells. Mechanistically, techniques such as ChIP-seq for p53 and FOXP3, combined with assays for histone methylation (e.g., H3K4me1/2/3) and comprehensive transcriptomic analysis via RNA-seq, would elucidate the direct molecular targets and downstream pathways regulated by [SETD9](/details-gene/133383) in these crucial immune-suppressive cells. **Therapeutic Potential:** As an enzyme, [SETD9](/details-gene/133383) is a potentially druggable target. Its role as an epigenetic regulator involved in p53 activity and immune function makes it a compelling candidate for therapeutic intervention in multiple diseases. In oncology, where aberrant methylation patterns and p53 dysregulation are common, small molecule inhibitors of [SETD9](/details-gene/133383) could represent a novel therapeutic strategy. Conversely, in the context of autoimmune diseases characterized by Treg dysfunction, strategies to enhance [SETD9](/details-gene/133383) activity could potentially restore immune homeostasis. The broad expression of [SETD9](/details-gene/133383) suggests that targeted delivery systems or cell-based therapies may be required to minimize off-target effects.

Genular Protein ID: 3950251763

Symbol: SETD9_HUMAN

Name: SET domain-containing protein 9

UniProtKB Accession Codes:

Q8NE22 F5H713

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ChEBI 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 2 Ensembl 2 ExpressionAtlas 1 GO 4 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 1 RefSeq 2 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 15372022

Title: The DNA sequence and comparative analysis of human chromosome 5.

PubMed ID: 15372022

DOI: 10.1038/nature02919

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

Sequence Information:

  • Length: 299
  • Mass: 34095
  • Checksum: 0CF616C68EDF2DC8
  • Sequence:
    • MPGRLLRGLW QRWRRYKYRF VPWIALNLSH NPRTLRYVPE ESKDKVISDE DVLGTLLKVF 
QALFLNDFNK QSEILSMLPE SVKSKYQDLL AVEHQGVKLL ENRHQQQSTF KPEEILYKTL 
GFSVAQATSS LISAGKGVFV TKGLVPKGAV VSMYPGTVYQ KYEPIFFQSI GNPFIFRCLD 
GVLIDGNDKG ISKVVYRSCN GRDRLGPLKM SDSTWLTSEI HNPLAVGQYV NNCSNDRAAN 
VCYQEFDVPA VFPIELKQYL PNIAYSYDKQ SPLRCVVLVA LRDINQGEEL FSNYYTIVS