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| Full Name | Lysine Methyltransferase 2C |
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| Symbol | KMT2C (formerly MLL3) |
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| Chromosomal Location | 7q36.1 |
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| NCBI Gene ID | [58508](https://www.ncbi.nlm.nih.gov/gene/58508) |
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| OMIM | [606833](https://www.omim.org/entry/606833) |
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| Ensembl ID | ENSG00000055607 |
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| UniProt ID | [Q9UMN6](https://www.uniprot.org/uniprot/Q9UMN6) |
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| Associated Diseases | Neurodevelopmental disorders, Kabuki syndrome, cancer |
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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.
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.
- 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
¶ Neurodegeneration and Neurodevelopment
-
Alzheimer's Disease
- KMT2C/MLL3 variants associated with AD risk
- Dysregulated H3K4 methylation in AD brain
- May affect expression of tau-related genes
- References: Cheng et al., 2018
-
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
-
Autism Spectrum Disorder
- KMT2C mutations identified in ASD cohorts
- Affects chromatin regulation of synaptic genes
- References: Stessman et al., 2017
- Frequently mutated in various cancers (head and neck, bladder, breast)
- Tumor suppressor function in some contexts
- Nuclear: Located in the nucleus
- Enrichment: Associated with enhancer regions
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
KMT2C activity is regulated by:
- Phosphorylation (multiple kinases)
- Acetylation (p300/CBP)
- Ubiquitination (various E3 ligases)
- Sumoylation
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 factor
KMT2C regulates transcription through:
- Enhancer Activation: H3K4me1 at enhancers
- Promoter Clearance: H3K4me3 at promoters
- Super-Enhancers: Critical for lineage-specific genes
KMT2C plays essential roles in brain development:
- Cortical Patterning:Establishes cortical identity
- Neuronal Migration: Regulates neuronal positioning
- Synaptogenesis: Controls synapse formation
- Myelination: Affects oligodendrocyte development
In the adult brain, KMT2C maintains:
- Cognitive Function: Memory and learning
- Synaptic Plasticity: Long-term potentiation
- Dendritic Arborization: Neuronal morphology
- KMT2C variants associated with AD risk
- Expression changes in AD brain
- Epigenetic dysregulation of H3K4 methylation
- Tau Pathology: KMT2C affects tau-related gene expression
- Amyloid Response: Alters inflammatory gene regulation
- Synaptic Genes: Dysregulates synaptic plasticity genes
Targeting KMT2C for AD:
- HDAC inhibitors (increase KMT2C activity)
- Small molecule activators
- Gene therapy approaches
- KMT2C expression altered in PD brain
- Role in dopaminergic neuron function
- Connection to LRRK2 pathway
| Condition |
KMT2C Association |
| Huntington's Disease |
H3K4 methylation dysregulation |
| Frontotemporal Dementia |
Epigenetic changes |
| ALS |
Altered expression |
| Agent |
Mechanism |
Development Stage |
| HDAC inhibitors |
Increase KMT2C activity |
Preclinical |
| KMT2C activators |
Direct activation |
Research |
| DPY30 mimics |
Enhance complex function |
Investigational |
AAV-mediated KMT2C delivery for neuroprotection.
KMT2C-/- mice:
- Embryonic lethal (complete loss)
- Brain-specific knockouts show cognitive deficits
Brain-specific deletion models show:
- Impaired memory formation
- Reduced synaptic plasticity
- Aberrant gene expression
KMT2C overexpression protects against:
KMT2C as a biomarker:
- H3K4me1 levels in CSF
- KMT2C expression in blood cells
Predicting disease progression:
- KMT2C expression as progression marker
- Treatment response predictions
Current research priorities:
- Understanding KMT2C in specific neuronal subtypes
- Developing brain-penetrant activators
- Biomarker development
- Combination therapies