KMT2C — Lysine Methyltransferase 2C

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

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

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

• 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)

• 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)

• 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

• Phosphorylation (multiple kinases)
• Acetylation (p300/CBP)
• Ubiquitination (various E3 ligases)
• Sumoylation

Molecular Pathways

COMPASS Complex

Transcriptional Regulation

• Enhancer Activation: H3K4me1 at enhancers
• Promoter Clearance: H3K4me3 at promoters
• Super-Enhancers: Critical for lineage-specific genes

Neurological Functions

Brain Development

Adult Brain Function

• 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

Therapeutic Potential

• 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

Animal Models

Knockout Mice

• Embryonic lethal (complete loss)
• Brain-specific knockouts show cognitive deficits

Conditional Knockouts

• Impaired memory formation
• Reduced synaptic plasticity
• Aberrant gene expression

Transgenic Models

• Cognitive decline
• Synaptic dysfunction
• [Neuroinflammation](/mechanisms/neuroinflammation)

Biomarkers

Diagnostic Potential

• H3K4me1 levels in CSF
• KMT2C expression in blood cells

Prognostic Potential

• KMT2C expression as progression marker
• Treatment response predictions

Research Directions

Current research priorities:

References

Cellular Functions

Chromatin Regulation

Transcriptional Coactivation

• 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

| Agent | KMT2C Effect | Clinical Use |
|-------|-------------|-----------|
| Vorinostat | Activation | FDA approved |
| Entinostat | Strong activation | Clinical trials |
| Panobinostat | Activation | Investigational |

Combination Approaches

| Primary | Secondary | Rationale |
|---------|-----------|----------|
| HDACi | KMT2C activator | Synergistic |
| HDACi | DNA methyltransferase | Dual targeting |
| KMT2C activator | BET inhibitor | Combined epigenetics |

Neurodegeneration Research

Model Systems

Biomarker Development

• H3K4me1: Histone mark in CSF
• KMT2C mRNA: Blood expression
• KMT2C protein: Tissue markers

Clinical Translation

Therapeutic Development

Challenges and Solutions

| Challenge | Solution |
|-----------|---------|
| Brain penetration | Lipophilic compounds |
| Specificity | Structure-based design |
| Delivery | AAV vectors |
| Biomarkers | Develop assays |

Additional References

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

Pathway Diagram

The following diagram shows the key molecular relationships involving KMT2C — Lysine Methyltransferase 2C discovered through SciDEX knowledge graph analysis: