# Deciphering the molecular mechanisms of histone code recognition by ATAD2/B

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2022 · $10,140

## Abstract

ATAD2 is an important co-activator of the estrogen and androgen receptors. ATAD2 is known to be up-
regulated in multiple different types of cancer including breast, lung, gastric, endometrial, renal, and prostate.
Up-regulation of ATAD2 is often correlated with poor patient outcomes, and can be used as prognostic marker.
Furthermore, silencing the expression of ATAD2 through RNA interference inhibits cell proliferation and
promotes apoptosis in ovarian carcinoma, and inhibits migration and invasion of hepatocellular carcinoma and
colorectal cancer cells. ATAD2B, is a poorly studied paralog of the ATAD2 gene, and although ATAD2 and
ATAD2B are highly conserved, there is little known about the function of ATAD2B or its role in oncogenesis.
Both the ATAD2/B proteins contain two conserved domains: an AAA ATPase domain and a bromodomain. The
overall objective of the proposed research is to determine how di-acetyllysine recognition by the ATAD2/B
bromodomains regulates the cellular function of these proteins. This proposal aims to: (1) characterize how
cross-talk between histone modifications modulate acetyllysine recognition by the ATAD2/B bromodomains; (2)
outline the molecular mechanism(s) of di-acetylated histone recognition by the ATAD2/B bromodomains; (3)
determine the functional significance of di-acetyllysine recognition by the ATAD2/B bromodomains. A unique
combination of in vitro biochemical, biophysical, and structural biology studies on the ATAD2/B bromodomains
will be coupled with in vivo functional genomic investigations using a breast cancer progression model to
characterize the biological roles of the ATAD2/B bromodomains. We will evaluate the impact of neighboring
histone modifications on histone H4 tail recognition using peptide array assays in combination with isothermal
titration calorimetry (ITC) and nuclear magnetic resonance (NMR) chemical shift perturbation techniques. We
will determine the structural features of ATAD2/B bromodomains required for recognition of di-acetylated
histone tail ligands using NMR and/or X-ray crystallography. To characterize the binding mode of the ATAD2/B
bromodomains with their histone ligands we will carry out analytical ultracentrifugation, size-exclusion
chromatography, ITC, and NMR T1/T2 relaxation experiments. Site-directed mutagenesis coupled with NMR
and ITC will be used to measure the effects on ligand binding, and identify differences in the binding pockets of
the ATAD2/B bromodomains. We will compare the genome-wide associations of ATAD2/B with histone H4
acetylation patterns in a breast cancer progression model to determine the impact of ATAD2/B on breast
cancer cell phenotypes using ChIP-seq and RNA-seq, followed by cellular migration and invasion assays. Our
multi-faceted approach will correlate specific histone modifications with ATAD2/B binding and action, which will
allow us to connect histone H4 acetylation marks to bromodomain function in cancer cell proliferation. Overall,
our integ...

## Key facts

- **NIH application ID:** 10592912
- **Project number:** 3R01GM129338-04S2
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Seth E Frietze
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $10,140
- **Award type:** 3
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592912

## Citation

> US National Institutes of Health, RePORTER application 10592912, Deciphering the molecular mechanisms of histone code recognition by ATAD2/B (3R01GM129338-04S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10592912. Licensed CC0.

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