Restricted Research - Award List, Note/Discussion Page

Fiscal Year: 2018

2006  The University of Texas at San Antonio  (75824)

Principal Investigator: Ruan, Jianhua (Principal Investigator)  

Total Amount of Contract, Award, or Gift (Annual before 2011): $ 424,685

Exceeds $250,000 (Is it flagged?): Yes

Start and End Dates: 3/1/17 - 2/28/22

Restricted Research: YES

Academic Discipline: COS COMPUTER SCIENCE  

Department, Center, School, or Institute: COS COMPUTER SCIENCE  

Title of Contract, Award, or Gift: Systems Analysis of Epigenomic Architecture in Endocrine-Resistant Cancers - Project 1

Name of Granting or Contracting Agency/Entity: Univ of TX HSC at San Antonio 745

Program Title: N/A

Note:

Endocrine therapy is commonly used in hormone-driven breast and prostate cancers. A persistent challenge is disease progression caused by endocrine resistance during the treatment. Studies for the past 25 years have revealed the essential roles 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 endocrine resistance. However, the molecular mechanisms underlying enhancer-regulated hormone resistance transition are largely unknown. It was recently discovered that the most active and functionally important ER enhancers recruited 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 also show the presence of MegaTrans TFs in AR-bound enhancers. Because most MegaTrans TFs themselves are signaling-dependent molecules. They can play as relay factors to sensitize the influence of signals from cancer microenvironment. Thus, the combinatorial interactions between ER/AR and MegaTrans TFs make ER/AR-bound enhancers respond not only to estrogen and androgen, but also to other signals from cancer microenvironment. The hypothesis is that the composition and interaction of MegaTrans undergo dynamic changes during cancer progression, resulting in alterations of ER/AR enhancer functions that promote endocrine-resistance in breast or prostate cancer cells. In this project, in Aim 1, a biotin-tagged approach is coupled with different omics profiling experiments to understand the dynamic changes of MegaTrans TFs during hormone resistance transition and their binding patterns at ER/AR-bound enhancers. Also GRO-seq is used 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 with MegaTrans TFs. In Aim2, different computational algorithms will be used to model the changes of ER/AR-regulated transcription programs that are dependent on different combinations of MegaTrans TFs and other cis-binding factors. We will also computationally characterize the combinatorial interaction patterns of different TFs and DNA and correlate signaling network or microenvironmental cue changes with MegaTrans component to predict them as candidate drivers of endocrine resistance and metastasis. In Aim3, CRISP/Cas9 genome-editing and single cell technology will prove the functional linkage of MegaTrans TFs and hormone resistance and metastasis. Consistent with the priority of Cancer Systems Biology Consortium, these studies will prove insights into the characteristic or epigenetic changes of ER/AR-bound enhancers that are influenced by different microenvironmental cues

Discussion:

yes 8.1.18jn

 

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