Chromatin regulation of breast stem/progenitor cells by Pygo
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Our understanding of breast cancer has been greatly advanced since the recent identification of breast cancer stem cells (BCSCs), a minor pool of transformed stem cells that can initiate new breast tumors. The presence of BCSCs may explain the cause of metastatic breast cancers and why cancers recur after being treated with available therapeutic agents that can shrink the tumor mass but cannot eliminate BCSCs. A better understanding of the molecular control of BCSCs and their physiological counterparts may provide new targets for more effective therapies. Wnt signaling plays a critical role in the self-renewal of both BCSCs and normal mammary gland stem/progenitor cells. Aberrant activation of Wnt signaling results in breast cancers with an expanded stem cell pool. Pygopus 2 (Pygo2) is a recently identified activator of the Wnt pathway. Deleting Pygo2 from the mouse genome leads to reduced Wnt signaling and compromised proliferation of breast stem/progenitor cells, suggesting that it may serve as a new molecular therapeutic target for interfering with breast stem cell activities. 
 
 
 
 
 
 
 
 In this project we will study the role of Pygo2 in chromatin remodeling of mammary epithelial cells. My preliminary studies implicate Pygo2 as a potential regulator of methylation and acetylation of histones, a group of small proteins that pack the long DNA molecules into repetitive units inside the cell nucleus. Epigenetic events such as histone modifications and DNA methylation have been linked to breast cancer. It has been proposed that cancer-associated epigenetic changes inactivate tumor suppressor genes. Drugs that may correct these epigenetic changes are being tested in clinical trials for cancer therapy. Before such epigenetic drugs become widely used for breast cancers, it is essential for us to understand how normal epigenetic patterns are established/maintained and how these alterations occur in breast cancer.
 
 
 
 
 
 
 
 Specifically, we will investigate how Pygo2 recognizes and binds to a specific type of histone modification (H3K4me3) on target chromatin, and in turn recruits protein complexes that have other histone modifying activities (e.g., acetylation). For these experiments, we will make specific changes (mutations) to the Pygo2 protein and test if they interfere with its ability to bind to modified histone (H3K4me3) or to the target chromatin. I will determine the functional consequences (e.g., histone modifications, target gene activation) of these mutations, as well as the mammary progenitor cell activities after knocking down Pygo2 protein (using a technique called RNA interference). Furthermore, I will purify and characterize the components of the Pygo2-containing protein complex using mass spectrometry analysis.
 
 
 
 
 
 
 
 We anticipate that successful completion of the proposed research will provide key molecular insights of how Wnt signaling controls breast stem/progenitor cell activities and may uncover a novel link between chromatin regulation, transcriptional control, and breast cancer stem cell activation.