# Elucidating the Functional Role of Post-translational Aminoacylation in Chromatin Regulation

> **NIH NIH F31** · HARVARD UNIVERSITY · 2024 · $40,689

## Abstract

PROJECT SUMMARY/ABSTRACT
Recent exome sequencing efforts have implicated alterations that occur within the actin-related proteins (Arps),
ACTL6A and ACTL6B, in both cancer and neurodevelopmental disorders. These highly conserved and tissue-
specific protein paralogues are subunits of multi-component molecular machines that use the energy derived
from ATP hydrolysis to modify chromatin architecture, and hence modulate gene expression. ACTL6A and
ACTL6B are subunits of four major chromatin regulators known to remodel the architecture of chromatin: (1) the
Tip60/NuA4 histone acetyl transferase, and the (2) INO80, (3) SRCAP, and (4) mammalian SWI/SNF
(mSWI/SNF), also called BRG1/BRM Associated Factors (BAF) ATP-dependent chromatin remodeling
complexes. The mSWI/SNF complex has been particularly implicated in a range of neurodevelopmental
disorders and in over 20% of all cancers. However, despite these intriguing genetic studies as well as data
suggesting that Arps are required for proper chromatin regulation, there is very little understanding regarding the
biochemical and genome-wide role of Arps in chromatin remodeling activities. My proposed research plan aims
to further our understanding of the molecular mechanisms of disease conferred by mutant ACTL6A and ACTL6B
by identifying functional regions and the biochemical and genome-wide activities of the Arps. Aim 1 investigates
the functional regions and biochemical activities contributed to chromatin remodeling complexes by ACTL6A and
ACTL6B in WT conditions and mutant settings linked with neurodevelopmental disorders. More specifically, Sub-
aim 1A seeks to compare the interactome of the ACTL6 subunits. Sub-aim 1B unbiasedly compares the protein
interactions of WT and mutant ACTL6A/B. Sub-aim 1C focuses on mSWI/SNF complexes to assess their histone
binding and enzymatic activities in WT forms and in those complexes bearing Arps with disease-relevant
mutations. Aim 2 dissects the genome-wide function of the Arps by comparing a WT control to induced
pluripotent stem cells (iPSCs) engineered to have disease-relevant mutations. Sub-aim 2A dissects the
chromatin accessibility and gene expression profiles of WT and mutant iPSCs. And, Sub-aim 2B looks at the
genome targeting of the mutant and WT ACTL6 subunits and the four major protein complexes known to bind
them. Successful completion of these aims will provide new insights regarding the interplay of chromatin
remodeling complexes unified by the same family of Arp proteins, define the molecular mechanisms of
ACTL6A/B-binding proteins in normal and disease states, and suggest novel targeted therapeutic approaches
for cancer and intellectual disabilities. The research laboratory of Dr. Cigall Kadoch is the ideal setting to conduct
the disease-oriented research at the interface between biochemistry and functional genomics detailed in this
proposal. Training in state-of-the-art biochemical, enzymatic, and genomic assays, as well as the professional
develop...

## Key facts

- **NIH application ID:** 10753533
- **Project number:** 5F31GM143896-03
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Jose Del Rio Pantoja
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,689
- **Award type:** 5
- **Project period:** 2022-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753533

## Citation

> US National Institutes of Health, RePORTER application 10753533, Elucidating the Functional Role of Post-translational Aminoacylation in Chromatin Regulation (5F31GM143896-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10753533. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*