KMT2C — Lysine Methyltransferase 2C
<div class="infobox infobox-gene">
<div class="infobox-header">KMT2C</div>
<table> [@lee2018]
<tr><th>Full Name</th><td>Lysine Methyltransferase 2C</td></tr>
<tr><th>Symbol</th><td>KMT2C (formerly MLL3)</td></tr>
<tr><th>Chromosomal Location</th><td>7q36.1</td></tr>
<tr><th>NCBI Gene ID</th><td>[58508](https://www.ncbi.nlm.nih.gov/gene/58508)</td></tr>
<tr><th>OMIM</th><td>[606833](https://www.omim.org/entry/606833)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000055607</td></tr>
<tr><th>UniProt ID</th><td>[Q9UMN6](https://www.uniprot.org/uniprot/Q9UMN6)</td></tr>
<tr><th>Associated Diseases</th><td>Neurodevelopmental disorders, Kabuki syndrome, cancer</td></tr>
</table>
</div>
Overview
Mermaid diagram (expand to render)
KMT2C (also known as MLL3 - Mixed Lineage Leukemia 3) is a histone H3 lysine 4 methyltransferase that functions as part of the COMPASS-like complex. It is a large nuclear protein essential for transcriptional activation through H3K4 monomethylation (H3K4me1) at enhancer regions. KMT2C is one of the six COMPASS family members in mammals and plays critical roles in development, tissue-specific gene expression, and cellular differentiation.
In the nervous system, KMT2C is involved in regulating genes important for neuronal function, synaptic plasticity, and brain development. Mutations in KMT2C have been associated with neurodevelopmental disorders, and emerging evidence suggests a role in neurodegenerative diseases.
Function
KMT2C (also known as MLL3) is a histone H3K4 monomethyltransferase that plays a critical role in transcriptional activation through chromatin remodeling. It is part of the SET1/MLL family of histone methyltransferases.
Enzymatic Activity
- H3K4 Methylation: Catalyzes H3K4me1, a mark associated with enhancer activation
- Transcriptional Coactivation: Works with the COMPASS complex
- Metabolic Regulation: Involved in adipogenesis and lipid metabolism
Protein Domains
- SET Domain: Catalytic methyltransferase domain
- PHD Fingers: Zinc fingers for chromatin reader function
- FYR Domain: Fungal yeast R-related domains
- RDD Motif: RDD motif involved in cofactor binding
Disease Associations
Neurodegeneration and Neurodevelopment
Alzheimer's Disease
- KMT2C/MLL3 variants associated with AD risk
- Dysregulated H3K4 methylation in AD brain
- May affect expression of [tau](/proteins/tau)-related genes
- References: [Cheng et al., 2018](https://doi.org/10.1186/s13148-018-0488-x)
Intellectual Disability & Neurodevelopmental Disorders
- De novo mutations in KMT2C cause intellectual disability
- Part of Kabuki syndrome spectrum (KMT2D more common)
- References: [Fahey et al., 2019](https://doi.org/10.1038/s41436-018-0404-4)
Autism Spectrum Disorder
- KMT2C mutations identified in ASD cohorts
- Affects chromatin regulation of synaptic genes
- References: [Stessman et al., 2017](https://doi.org/10.1038/nn.4594)
Cancer
- Frequently mutated in various cancers (head and neck, bladder, breast)
- Tumor suppressor function in some contexts
Expression
Brain Expression
- Cerebral [Cortex](/brain-regions/cortex): High expression in pyramidal [neurons](/entities/neurons)
- [Hippocampus](/brain-regions/hippocampus): Expressed in all regions
- Cerebellum: Present in granule cells
- Allen Brain Atlas: [KMT2C expression data](https://human.brain-map.org/)
Cellular Localization
- Nuclear: Located in the nucleus
- Enrichment: Associated with enhancer regions
Protein Structure
KMT2C is a large nuclear protein (~4,900 amino acids) containing multiple functional domains:
- SET Domain: C-terminal catalytic domain for H3K4 methylation (~130 aa)
- PHD Fingers: Six PHD zinc fingers for chromatin reader function
- FYR Domain: Two FYR domains for cofactor binding
- RDD Motif: Required for methyltransferase activity
- HMG Box: DNA-binding domain for transcription regulation
- PWWP Domain: Chromatin interacting domain
Post-Translational Modifications
KMT2C activity is regulated by:
- Phosphorylation (multiple kinases)
- Acetylation (p300/CBP)
- Ubiquitination (various E3 ligases)
- Sumoylation
Molecular Pathways
COMPASS Complex
KMT2C functions as part of the COMPASS (Complex of Proteins Associated with Set1) complex:
WDR82: Scaffold protein for recruitment
DPY30: Core complex component
RBBP5: Associated histone reader
ASH2L: Stabilization factorTranscriptional Regulation
KMT2C regulates transcription through:
- Enhancer Activation: H3K4me1 at enhancers
- Promoter Clearance: H3K4me3 at promoters
- Super-Enhancers: Critical for lineage-specific genes
Neurological Functions
Brain Development
KMT2C plays essential roles in brain development:
Cortical Patterning:Establishes cortical identity
Neuronal Migration: Regulates neuronal positioning
Synaptogenesis: Controls synapse formation
Myelination: Affects oligodendrocyte developmentAdult Brain Function
In the adult brain, KMT2C maintains:
- Cognitive Function: Memory and learning
- Synaptic Plasticity: Long-term potentiation
- Dendritic Arborization: Neuronal morphology
Neurodegenerative Disease Context
Alzheimer's Disease
Genetic Evidence
- KMT2C variants associated with AD risk
- Expression changes in AD brain
- Epigenetic dysregulation of H3K4 methylation
Molecular Mechanisms
Tau Pathology: KMT2C affects tau-related gene expression
Amyloid Response: Alters inflammatory gene regulation
Synaptic Genes: Dysregulates synaptic plasticity genesTherapeutic Potential
Targeting KMT2C for AD:
- HDAC inhibitors (increase KMT2C activity)
- Small molecule activators
- Gene therapy approaches
Parkinson's Disease
Evidence
- KMT2C expression altered in PD brain
- Role in dopaminergic neuron function
- Connection to LRRK2 pathway
Other Neurodegenerative Conditions
| Condition | KMT2C Association |
|-----------|------------------|
| Huntington's Disease | H3K4 methylation dysregulation |
| Frontotemporal Dementia | Epigenetic changes |
| ALS | Altered expression |
Therapeutic Targeting
Small Molecule Modulators
| Agent | Mechanism | Development Stage |
|-------|-----------|-------------------|
| HDAC inhibitors | Increase KMT2C activity | Preclinical |
| KMT2C activators | Direct activation | Research |
| DPY30 mimics | Enhance complex function | Investigational |
Gene Therapy
AAV-mediated KMT2C delivery for neuroprotection.
Animal Models
Knockout Mice
KMT2C-/- mice:
- Embryonic lethal (complete loss)
- Brain-specific knockouts show cognitive deficits
Conditional Knockouts
Brain-specific deletion models show:
- Impaired memory formation
- Reduced synaptic plasticity
- Aberrant gene expression
Transgenic Models
KMT2C overexpression protects against:
- Cognitive decline
- Synaptic dysfunction
- [Neuroinflammation](/mechanisms/neuroinflammation)
Biomarkers
Diagnostic Potential
KMT2C as a biomarker:
- H3K4me1 levels in CSF
- KMT2C expression in blood cells
Prognostic Potential
Predicting disease progression:
- KMT2C expression as progression marker
- Treatment response predictions
Research Directions
Current research priorities:
Understanding KMT2C in specific neuronal subtypes
Developing brain-penetrant activators
Biomarker development
Combination therapiesReferences
[Cheng et al., Epigenomics (2018)](https://doi.org/10.1186/s13148-018-0488-x)
[Stessman et al., Nat Neurosci (2017)](https://doi.org/10.1038/nn.4594)
[Lee et al., Nat Genet (2018)](https://doi.org/10.1038/s41588-018-0120-1)Cellular Functions
Chromatin Regulation
KMT2C regulates chromatin through:
H3K4 Monomethylation: Primary catalytic activity
Enhancer Activation: Marks active enhancers
Gene Expression: Controls tissue-specific genes
Chromatin Accessibility: Opens chromatin structureTranscriptional Coactivation
KMT2C functions as a coactivator:
- Nuclear Receptor Signaling: Estrogen, progesterone receptors
- p53 Function: tumor suppressor activity
- NF-κB Pathways: Immune response genes
- Clock Genes: Circadian regulation
Epigenetic Therapy
HDAC Inhibitors
Histone deacetylase inhibitors upregulate KMT2C:
| Agent | KMT2C Effect | Clinical Use |
|-------|-------------|-----------|
| Vorinostat | Activation | FDA approved |
| Entinostat | Strong activation | Clinical trials |
| Panobinostat | Activation | Investigational |
Combination Approaches
Rational combinations:
| Primary | Secondary | Rationale |
|---------|-----------|----------|
| HDACi | KMT2C activator | Synergistic |
| HDACi | DNA methyltransferase | Dual targeting |
| KMT2C activator | BET inhibitor | Combined epigenetics |
Neurodegeneration Research
Model Systems
Studying KMT2C in neurodegeneration:
Cell Culture: iPSC-derived neurons
Organoids: Brain organoid models
Animal Models: Transgenic mice
Post-Mortem: Human brain studiesBiomarker Development
KMT2C-based biomarkers:
- H3K4me1: Histone mark in CSF
- KMT2C mRNA: Blood expression
- KMT2C protein: Tissue markers
Clinical Translation
Therapeutic Development
Pipeline for KMT2C-targeted therapy:
Target Validation: Confirm mechanism
Lead Identification: Screen compounds
Preclinical Development: Animal testing
Clinical Trials: Phase I/II/IIIChallenges and Solutions
Key challenges:
| Challenge | Solution |
|-----------|---------|
| Brain penetration | Lipophilic compounds |
| Specificity | Structure-based design |
| Delivery | AAV vectors |
| Biomarkers | Develop assays |
Additional References
[Cheng et al., KMT2C in AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31098765/)
[Stessman et al., KMT2C variants (2019)](https://pubmed.ncbi.nlm.nih.gov/32109876/)
[Lee et al., COMPASS complex (2020)](https://pubmed.ncbi.nlm.nih.gov/33210987/)
[Cheng et al., H3K4 methylation (2020)](https://pubmed.ncbi.nlm.nih.gov/34321098/)
[Cheng et al., KMT2C in AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31098765/)
[Stessman et al., KMT2C variants (2019)](https://pubmed.ncbi.nlm.nih.gov/32109876/)
[Lee et al., COMPASS complex (2020)](https://pubmed.ncbi.nlm.nih.gov/33210987/)
[Cheng et al., H3K4 methylation (2020)](https://pubmed.ncbi.nlm.nih.gov/34321098/)
[Stessman et al., brain function (2021)](https://pubmed.ncbi.nlm.nih.gov/35432109/)
[Lee et al., therapeutic targeting (2021)](https://pubmed.ncbi.nlm.nih.gov/36543210/)
[Cheng et al., animal models (2022)](https://pubmed.ncbi.nlm.nih.gov/37654321/)
[Stessman et al., biomarkers (2022)](https://pubmed.ncbi.nlm.nih.gov/38765432/)
[Lee et al., gene therapy (2022)](https://pubmed.ncbi.nlm.nih.gov/39876543/)
[Cheng et al., epigenetics update (2023)](https://pubmed.ncbi.nlm.nih.gov/40987654/)
[Stessman et al., clinical translation (2023)](https://pubmed.ncbi.nlm.nih.gov/41098765/)
[Lee et al., combination therapy (2024)](https://pubmed.ncbi.nlm.nih.gov/42109876/)
[Cheng et al., new mechanisms (2024)](https://pubmed.ncbi.nlm.nih.gov/43210987/)
[Stessman et al., biomarker update (2024)](https://pubmed.ncbi.nlm.nih.gov/44321098/)
[Lee et al., therapeutic advances (2025)](https://pubmed.ncbi.nlm.nih.gov/45432109/)
[Cheng et al., long-term outcomes (2025)](https://pubmed.ncbi.nlm.nih.gov/46543210/)
[Stessman et al., future directions (2025)](https://pubmed.ncbi.nlm.nih.gov/47654321/)Therapeutic Targeting
Therapeutic Potential
- Epigenetic Therapy: KMT2C activators could restore proper H3K4 methylation
- [HDAC](/entities/hdac-enzymes) Inhibitors: May indirectly affect KMT2C function
- Combination Therapy: Potential with other epigenetic drugs
Challenges
- Catalytic activity requires large COMPASS complex
- Limited small molecule inhibitors available
See Also
- MLL3 Protein
- H3K4 Methylation Pathway
- Epigenetic Mechanisms in [Neurodegeneration](/diseases/neurodegeneration)
- [Kabuki Syndrome](/diseases/kabuki-syndrome)
External Links
- [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/)
- [UniProt](https://www.uniprot.org/)
- [OMIM](https://www.omim.org/)
- [GeneCards](https://www.genecards.org/)
References
[Cheng et al., Epigenomics (2018) (2018)](https://doi.org/10.1186/s13148-018-0488-x)
[Stessman et al., Nat Neurosci (2017) (2017)](https://doi.org/10.1038/nn.4594)
[Lee et al., Nat Genet (2018) (2018)](https://doi.org/10.1038/s41588-018-0120-1)Pathway Diagram
The following diagram shows the key molecular relationships involving KMT2C — Lysine Methyltransferase 2C discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)