# Project 3 Topological mapping of chromatin architectures for hormone-independent gene transcription

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

## Abstract

ABSTRACT/SUMMARY - Project 3 
 Topological mapping of chromatin architectures for hormone-independent gene transcription 
Long-range chromatin interactions between ERα/AR-bound enhancers and promoters are necessary for 
coordinated gene regulation in breast and prostate cancer cells. These interactions occur via the formation of 
3D chromatin architecture that brings enhancers and transcription factor complexes into close contact with 
target genes. To decode this complex regulation, we and other investigators have previously used Hi-C to map 
topologically associated domains (TADs) in different cell types. In a further study, we have identified a cancer- 
specific TAD on chromosome 17q23 that can be partitioned into an Eα-regulated transcription hub. 
Concordant up-regulation of its target genes is found to be associated with short disease-free survival in a 
subgroup of ERα-positive breast cancer patients, irrespective of their anti-hormone treatments. Emerging 
evidence has also shown AR-specific TADs are present in the prostate cancer cell genome. Therefore, we 
hypothesize that 1) frequent hormone (i.e., estrogen or androgen) stimulation leads to the formation of 
ERα/AR-related TADs that dynamically regulate transcription of multiple genes for aberrant proliferation of 
breast and prostate cancer cells and 2) in the presence of antagonists, a subset of these chromatin domains, 
herein termed transition TADs, continue to be exploited through chromatin redeployment for hormone- 
independent transcription. Whereas the majority of ERα/AR-related TADs are functionally suppressed by 
antagonists, transition TADs may partially escape this blockade for constitutive regulation of gene transcription. 
To test these hypotheses, we will use a modified Hi-C method, called tethered conformation capture (TCC), to 
investigate dynamic changes of TAD structures in hormone-sensitive and -resistant cancer cell lines exposed 
to agonists or antagonists (Aim 1). ChIP-seq of repressive, active, and gene-body histone marks and CTCF 
insulator will also be conducted in this cell line panel. MNase-seq and MBDCap-seq datasets will be acquired 
to map euchromatinized and heterochromatinized TADs. To integrate omics-seq data, we will develop a 
computational model, PRAM3D, which applies a Poisson Random effect Architecture Model (PRAM) to 
recapitulate 3D chromatin architectures (Aim 2). A Bayesian hierarchical model will predict putative transition 
TADs that concordantly regulate hormone-independent transcription of target genes. Furthermore, we will use 
a nucleosome density method to classify transition TAD subdomains into different regulatory categories, i.e., 
active, repressive, or bivalent transcription hubs. CRISPR/Cas9 genome-editing of critical chromatin regions 
may functionally disassemble spatiotemporal organization of these TAD-associated hubs (Aim 3). Proliferation 
and invasion/migration assays will determine whether this genome editing partially re-s...

## Key facts

- **NIH application ID:** 10151550
- **Project number:** 5U54CA217297-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Victor Jin
- **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/10151550

## Citation

> US National Institutes of Health, RePORTER application 10151550, Project 3 Topological mapping of chromatin architectures for hormone-independent gene transcription (5U54CA217297-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10151550. Licensed CC0.

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