Despite their discovery 35 years ago, enhancers continue to offer new fundamental insights into biology and disease. Recently, enhancer malfunction is emerging as a critical cause of human cancers. Targeting enhancers may offer novel, precision therapies for cancer treatment, which requires a deeper understanding of their action mechanisms. However, how enhancers are activated or repressed for gene regulation, how they form chromatin interaction with target regions, and how these events associate with human cancers remain largely unresolved questions. I focus on studying estrogen receptor alpha (ER?) regulated gene transcription program in breast cancer cells, with a long term goal to contribute to solving these questions. Overexpressed in ~75% of all breast cancers, ER? is the master transcription factor for BrCa gene expression, which preferentially act through binding enhancers. Unexpectedly, our recent data uncovered that ER?-regulated breast cancer enhancers display recruitment of the condensin complexes, which is required for coactivator/corepressor exchange and enhancer RNA (eRNA) transcription. Considering well-established roles of condensins on mitotic chromatin architecture, our findings and preliminary results offer a unique opportunity to test a hypothesis that enhancer-bound condensin complexes create/maintain specific and dynamic chromatin interactions of enhancers permissive to ligand-regulated transcriptional programs in ER?+ BrCa cells, at least in part, by linking active enhancers to specific sub-nuclear architectures. Specifically, this proposal aims to 1) identify a role of condensins in regulating dynamic ER?-dependent enhancer interaction network; 2) uncover a condensin-dependent mechanism by which active enhancers are tethered to specific sub-nuclear architecture for their activation; 3) elucidate potential function of condensins in the therapeutic responsiveness of BrCas to antiestrogen treatment. The major innovation of this proposal is that it uncovers a new component of the regulatory machinery underlying estrogen transcriptional program, in which at least a subset of regulatory enhancers are selectively activated due to their association with the nuclear pore complexes in a condensin-dependent manner, which also permits the formation of enhancer interaction network. This basic mechanism of regulated enhancer action would be likely applicable to other systems, and may be responsible for gene co-regulation by rapid signaling. In addition, our study has potential to establish condensin complexes as new prognostic marks of breast cancer progression, and important regulators of antiestrogen resistance. Therefore, this study has broad mechanistic and therapeutic implications.
As enhancer malfunction is emerging as a critical paradigm underlying gene deregulation in human cancers, deeper understanding of enhancer action mechanisms holds promise to develop novel, precision therapies for cancer treatment. Using a model of estrogen receptor alpha regulated transcriptional program in breast cancer cells, the proposed study in this application aims to provide an innovative mechanism that the dynamic recruitment of condensin complexes to estrogen regulated enhancers, and its interaction with the nuclear pore complex, is required for enhancer activation and formation of chromatin interaction network. This project has great potential to elucidate the molecular basis of enhancer and chromatin architectural control of gene transcription in breast cancer, as well as their link to tamoxifen resistance, with broad mechanistic and therapeutic implications.
