# The role of chromatin regulators in neurodevelopmental disorders

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $580,045

## Abstract

Abstract
 We propose to investigate the role of the chromatin methyltransferase DOT1L in neuronal function and
determine how its disruption leads to neurodevelopmental disorders (NDD). Although the genetic causes of
NDDs are heterogeneous, a high proportion of causative mutations are within the genes that encode chromatin
regulators. Chromatin is the complex of DNA and the histone proteins that organize the genome and control
gene expression. Chromatin regulating enzymes deposit a wide range of posttranslational modifications on
histones such as methylation, acetylation, and many others. Interestingly, recent advances have identified
mutations in the histone methyltransferase DOT1L in NDD patients with intellectual disability and
developmental delays. However, the mechanisms through which DOT1L functions in the brain remain largely
unknown. DOT1L is the sole methyltransferase of histone 3 lysine 79 where it deposits methylation marks
(H3K79me). Patient mutations are de novo, monoallelic, and cluster in the catalytic domain. Our preliminary
data indicate that they likely act as loss-of-function mutations and decrease methylation of H3K79. In addition,
we found that DOT1L and H3K79me increase during neuronal development and that DOT1L depletion affects
transcription of critical neuronal synaptic genes. Together, this work suggests that DOT1L plays a critical role
in neuronal development and function.
 We hypothesize that partial loss of DOT1L and H3K79me disrupt transcription leading to cognitive
deficits and changes in neuronal maturation and synaptic gene expression. To test this, we will bring together
biochemical studies, genome-wide sequencing, and new cell and mouse lines to generate a model of the
patient disorder and define the function of H3K79me in neurons. Merging new systems with a wide range of
approaches has the potential to define how DOT1L affects cognition. We will first employ a heterozygous Dot1l
knockout mouse model to examine how partial loss of DOT1L affects chromatin, transcription, neurogenesis,
neuronal maturation, and behavior to provide insights into the disorder. Next, we will focus on H3K79me using
a new mutant embryonic stem cell line that allows us to specifically examine the effects of H3K79me in
differentiated neurons without perturbing other functions of DOT1L. We will use this stem cell model to
measure H3K79me genomic localization during neuronal development and determine how H3K79me loss
affects transcription and neuronal differentiation. By merging these diverse approaches, we will expand our
understanding of both an emerging disorder and the role and regulation of H3K79me in neurons. In addition,
these experiments will contribute to the broader understanding of how epigenetic regulators play a role in brain
function and how their disruption leads to neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10981097
- **Project number:** 1R01NS134755-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Erica Megan Korb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $580,045
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981097

## Citation

> US National Institutes of Health, RePORTER application 10981097, The role of chromatin regulators in neurodevelopmental disorders (1R01NS134755-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981097. Licensed CC0.

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