# Exploring the functional role of tubulin methylation and its regulation by mes-4/NSD in C. elegans

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

ABSTRACT
The microtubule cytoskeleton serves many critical functions in the cell, and its dysfunction is linked to a plethora
of diseases from cancer to neurodevelopmental disorders such as autism. Post-translational modifications (PTM)
of the tubulin subunits of microtubules are key regulators of both structure and function of microtubules. Similar
to the “Histone Code”, the “Tubulin Code” hypothesis posits microtubule function is tuned through the
incorporation of specific tubulin isoforms and PTMs. Methylation is well known as a common PTM on histones,
however, the function of tubulin methylation and the enzymatic machinery that “reads, writes and erases” this
PTM on microtubules has been largely unexplored. We have identified a new role for the histone-
methyltransferase NSD3 as a tubulin methyltransferase that di-methylates -tubulin at lysines 96 and 112 (the
K96me2 and K112me2 marks). I am exploring the in vivo role of these new methyl marks on -tubulin utilizing
the model organism C. elegans. I have now discovered the NSD3 orthologue in the worm, mes-4, has a somatic
role in neurons, leading me to hypothesize loss of mes-4 abrogates α-tubulin methylation at K96 and K112,
resulting in defects in organization and function of the neuronal cytoskeleton. To test this hypothesis in Aim1 I
will explore the function of K96me2 and K112me2 in the worm utilizing methyl-deficient knockin tubulin mutations
to understand how lack of methylation at these sites impacts microtubule structure (Aim1.1) and dynamics
(Aim1.2). In Aim 2, I will further determine if loss of mes-4 causes loss of K96me2 and/or K112me2 using imaging
and biochemical techniques (Aim2.1-2.2). Studies exploring the role of these methyl marks using loss of function
approaches will be complemented by mes-4 gain of function studies (Aim 2.3). Many human cancers are driven
by mutations that over/constitutively activate NSD3. I will generate a mes-4 mutant worm carrying the same
mutation at the corresponding (conserved) site in C. elegans seen in human cancers, to ask if mes-4 hyperactivity
induces cytoskeletal and functional deficits. My doctoral dissertation will thoroughly investigate a new
perspective on how epigenetic machinery regulates the cytoskeleton, with far reaching implications for
understanding the many diseases linked to cytoskeletal defects.

## Key facts

- **NIH application ID:** 10906657
- **Project number:** 5F31GM151846-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Edward Pietryk
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906657

## Citation

> US National Institutes of Health, RePORTER application 10906657, Exploring the functional role of tubulin methylation and its regulation by mes-4/NSD in C. elegans (5F31GM151846-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10906657. Licensed CC0.

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