- 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 ER?/AR- bound enhancers that are influenced by different microenvironmental cues during the progression from hormone-sensitive to hormone-resistant cancers.
- Project 1 Endocrine therapies are commonly used to treat hormone-related cancers such as breast and prostate cancers. However, resistance to these therapies is a persistent challenge. The objective of this proposal is to understand dynamic changes of ER?/AR-bound enhancers during cancer progression. The knowledge gained will increase our ability to assess therapeutic responsiveness in breast and prostate cancers.
|Li, Tianbao; Liu, Qi; Garza, Nick et al. (2018) Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing. Genome Med 10:30|
|Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro E et al. (2018) Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2-ER?-GREB1 Transcriptional Axis. Cancer Res 78:671-684|
|Horning, Aaron M; Wang, Yao; Lin, Che-Kuang et al. (2018) Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle-Related Transcription and Attenuated Androgen Response. Cancer Res 78:853-864|
|Chen, Zhong; Wu, Dayong; Thomas-Ahner, Jennifer M et al. (2018) Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proc Natl Acad Sci U S A 115:6810-6815|
|Su, Jianzhong; Huang, Yung-Hsin; Cui, Xiaodong et al. (2018) Homeobox oncogene activation by pan-cancer DNA hypermethylation. Genome Biol 19:108|
|Zhu, Xinjie; Zhang, Qiang; Ho, Eric Dun et al. (2017) START: a system for flexible analysis of hundreds of genomic signal tracks in few lines of SQL-like queries. BMC Genomics 18:749|
|Gao, Zhen; Ruan, Jianhua (2017) Computational modeling of in vivo and in vitro protein-DNA interactions by multiple instance learning. Bioinformatics 33:2097-2105|
|Tang, Binhua; Cheng, Xiaolong; Xi, Yunlong et al. (2017) Advances in Genomic Profiling and Analysis of 3D Chromatin Structure and Interaction. Genes (Basel) 8:|
|Lin, Xueqiu; Su, Jianzhong; Chen, Kaifu et al. (2017) Sparse conserved under-methylated CpGs are associated with high-order chromatin structure. Genome Biol 18:163|
|Jadhav, Rohit R; Santucci-Pereira, Julia; Wang, Yao V et al. (2017) DNA Methylation Targets Influenced by Bisphenol A and/or Genistein Are Associated with Survival Outcomes in Breast Cancer Patients. Genes (Basel) 8:|
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