# Dissecting Histone H3K4 Methylation Enzymes in Neuroplasticity

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $659,441

## Abstract

Abstract
 One of the long-held mysteries in chromatin signaling is the excessive number of enzymes that install
or remove a single chromatin mark. The most extreme case is histone H3 lysine 4 (H3K4me) methylation, a
hallmark of transcriptionally active chromatin areas. H3K4me can be placed by six writer enzymes and
removed by six eraser enzymes, most of which are expressed broadly in all cell types of the brain and other
tissues. Strikingly, 10 of these 12 enzymes are responsible for monogenic forms of neurodevelopmental
disorders. These enzymes thus have non-redundant yet poorly understood roles in cognitive development and
function. Why do our brains need this many enzymes for the single histone mark?
 Cognitive function critically relies on a neural network's capability to rewire in response to sensory
inputs. However, the same network needs to maintain its excitability within an optimal range; otherwise, the
continuous sensory inputs or lack thereof could lead to excessive neuronal activity or inactivity, harmful to the
brain functions. Synaptic scaling is believed to be a way to meet the two competing demands. In response to
sustained hyperactivity, neurons scale down the receptivity to excitatory neurotransmitters. Conversely,
prolonged network inactivity causes neurons to scale up and increase synaptic efficacy. Prior studies revealed
that transcription in response to activity shifts is necessary for synaptic scaling. We now know several
chromatin regulators essential in the process. However, we know very little about the roles of histone H3K4me
enzymes in synaptic scaling.
 Our goal is to determine the roles of this prominent family of histone H3K4me enzymes in synaptic
scaling. The research team combines expertise in chromatin biology (Iwase lab.) and synaptic plasticity
(Sutton lab.) to attain this goal. We will test the hypothesis that H3K4me writer enzymes and their functional
interaction with H3K4me eraser enzymes delineate distinct facets of synaptic scaling. To this end, the
research team will 1) Generate the division of labor map of the H3K4me writer enzymes in synaptic scaling, 2)
Explore the molecular mechanisms by which KMT2A, an H3K4me writer enzyme, governs induction of
synaptic scaling. 3) Determine the functional interactions between H3K4me writer and eraser enzymes in
synaptic plasticity and behavior.
 Completion of the proposed research will reveal how H3K4me signaling stabilizes the neural ensemble.
In addition, our work will shed light on how the evolving brains have coopted expanded families of H3K4me
enzymes to achieve an intricate balance of network excitability. The obtained knowledge will be a foundation
on which evidence-based therapeutics can develop for H3K4me-related neurodevelopmental disorders and
many other cognitive deficits with chromatin dysregulation.

## Key facts

- **NIH application ID:** 10889792
- **Project number:** 1R01MH133632-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Shigeki Iwase
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $659,441
- **Award type:** 1
- **Project period:** 2024-07-12 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889792

## Citation

> US National Institutes of Health, RePORTER application 10889792, Dissecting Histone H3K4 Methylation Enzymes in Neuroplasticity (1R01MH133632-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10889792. Licensed CC0.

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