# Project 1 High-order assembly of MegaTrans complexes for hormone-independent enhancer activation

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

## Abstract

ABSTRACT/SUMMARY - Project 1
 High-order assembly of MegaTrans complexes for hormone-independent enhancer activation
Endocrine therapy is commonly used in hormone-driven breast and prostate cancers. A persistent challenge is
disease progression caused by hormone resistance during the treatment. Studies for the past 25 years have
revealed an essential role of hormones (i.e., estrogen and androgen) and their receptors, ER and AR, in
cancer progression. Increased evidence indicates that epigenetic deregulation of ER/AR-bound enhancers
profoundly alters hormone-mediated transcription machineries, leading to the development of hormone
resistance. However, the molecular mechanisms underlying this hormone-resistance transition of enhancer
function are largely unknown. We have recently discovered that the most active and functionally important
ER-bound enhancers can recruit a large number of DNA-binding transcription factors through protein-protein
interactions. These newly identified ER `co-activators', termed MegaTrans transcription factors (TFs), are
required to activate ER-bound enhancers and also serve as a signature of functional enhancers. Our
preliminary data additionally show the presence of MegaTrans TFs in AR-bound enhancers. Because most
MegaTrans TFs are signaling-dependent molecules, they may receive other signals from tumor
microenvironments to alter enhancer functions. Thus, combinatorial interactions between ER/AR and
MegaTrans TFs make their enhancers respond not only to estrogen or androgen, but also to other
microenvironmental signals. We hypothesize that the composition and interaction of MegaTrans TFs undergo
dynamic changes during cancer progression, resulting in alterations of ER/AR enhancer functions that
promote hormone-resistance in breast and prostate cancer cells. In Aim 1, we will use a biotin-tagged
approach coupled with mass spectrometry and ChIP-seq to investigate dynamic changes of MegaTrans TFs
during hormone-resistance transition and their binding patterns at ER/AR-bound enhancers. We will also
use GRO-seq to define nascent RNAs that are differentially transcribed in hormone-sensitive vs. -resistant
conditions and use CLIP-seq to identify enhancer non-coding RNAs (eRNAs) that are functionally linked to
MegaTrans TFs. In Aim 2, we will use computational algorithms to model changes of ER/AR-regulated
transcription programs that are dependent on different combinations of MegaTrans TFs and other cis-binding
factors. Then, we will computationally characterize combinatorial interaction patterns of different TFs and
DNA and correlate these changes with signaling networks or microenvironmental cues. In Aim 3, we will use
CRISPR/Cas9 genome-editing and single-cell approaches to prove the functional linkage of candidate
MegaTrans drivers and hormone-resistance and metastasis. Consistent with the overall goal of our proposed
U54 center, these studies will provide insights into the characteristics or epigenetic changes of...

## Key facts

- **NIH application ID:** 10151548
- **Project number:** 5U54CA217297-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Zhijie Jason Liu
- **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/10151548

## Citation

> US National Institutes of Health, RePORTER application 10151548, Project 1 High-order assembly of MegaTrans complexes for hormone-independent enhancer activation (5U54CA217297-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10151548. Licensed CC0.

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