# Project 2 Fine-scale nucleosome repositioning of enhancers for hormone-independent genomic function

> **NIH NIH U54** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $293,849

## Abstract

ABSTRACT/SUMMARY - Project 2 
Fine-scale nucleosome repositioning of enhancers for hormone-independent genomic function 
The cognate receptors AR and ER can remain active for tumor progression after anti-hormone treatment for 
patients with prostate and breast cancers. Despite intensive efforts to elucidate the underlying mechanisms, 
little information is available concerning AR/ERα genomic function for promoting hormone resistance at the 
nucleosome level. In preliminary studies, we observed this genomic function is well orchestrated, relying on 
precise nucleosome organization within cis-bound enhancers for hormone-dependent transcription. 
Interestingly, we also found that this epigenetic mechanism can be hijacked by hormone-resistant cells to gain 
their growth and invasion advantages. Therefore, we hypothesize that altered nucleosome positions, or 
nucleosome repositioning, in and near AR/ERα-bound enhancers is being exploited for hormone-independent 
genomic function in advanced cancers. In Aim 1, we will conduct ChIP-ePENS and MNase-seq to 
comprehensively map nucleosome boundaries of AR/ERα-bound enhancers in a panel of hormone-sensitive 
and -resistant cancer cells. RNA-seq will be conducted to determine differential expression patterns of 
corresponding genes in these cell lines. The NucPat computational pipeline will be deployed to seamlessly 
process complex omics-seq data (Aim 2). We will use a Kernel Density Estimation algorithm to determine 
nucleosome positioning and spacing when AR or ERα establishes direct contact with its binding motif. Using a 
Hidden Markov model, we will identify active nucleosome states that maximize DNA-protein contact for 
AR/ERα genomic functions. In addition, pioneer factor FOXA1 and chromatin remodelers participate in this 
nucleosome repositioning even in the absence of agonists or in the presence of antagonists. To confirm this 
computational modeling in vivo, ChIP-ePENS and MNase-seq will be conducted in patient-derived xenograft 
(PDX) lines carrying hormone-sensitive and -resistant tumors (Aim 3). A nucleosome-phasing index (NPI) will 
be established to quantitatively assess the nucleosome states of AR/ERα redeployment in different PDX lines. 
This integrative omics analysis will be extended to a cohort of primary tumors, categorized into 
high- and low-risk groups. Again, we will calculate individual NPIs and correlate the data with clinicopathological features of 
patients. This translational study is intended to determine whether nucleosome phasing for AR/ERα 
redeployment is already present in high-risk primary tumors. Patients with this intrinsic phenotype are expected 
to have an adverse clinical outcome, irrespective of their anti-hormone treatments. Therefore, our proposed 
study will address a previously uncharacterized mechanism of hormone resistance and provide experimental 
evidence that nucleosome repositioning plays an integral role in redefining AR/ERα genomic function for 
advanc...

## Key facts

- **NIH application ID:** 10151549
- **Project number:** 5U54CA217297-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Qianben Wang
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $293,849
- **Award type:** 5
- **Project period:** 2017-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151549

## Citation

> US National Institutes of Health, RePORTER application 10151549, Project 2 Fine-scale nucleosome repositioning of enhancers for hormone-independent genomic function (5U54CA217297-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10151549. Licensed CC0.

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