Jamy C. Peng, Ph.D. - US grants

DESCRIPTION (provided by applicant): Stem cells can self-renew or differentiate into multiple cell types. These properties promise great therapeutic potentials in regenerative medicine. Understanding the molecular mechanisms regulating stem cell identity and maintenance will provide fundamental knowledge about human health and likely accelerate the use of stem cells in regenerative medicine. Epigenetic mechanisms regulate dynamic changes of gene expression profiles to influence stem cell self-renewal and differentiation. I am especially interested in investigating Polycomb Group (PcG)-mediated epigenetic regulation of stem cells. My previous work characterized a novel mechanism regulating a PcG complex, a key epigenetic modifier, during the transition from pluripotency to developmentally restricted cell fates. Currently, I am investigating PcG functions and their interaction with Piwi in Drosophila ovarian germline, which is tractable to genetic, genomic, molecular, as well as cell biological analyses. Piwi is a master regulator of germline stem cells. During the mentored phase, I will characterize Piwi-PcG interaction and determine how this interaction impacts Drosophila ovarian germline and germline stem cells. During the independent phase, I will characterize the molecular effects of PcG functions and Piwi-PcG interaction in Drosophila germline. This study will have significant impact on stem cell biology, epigenetics, as well as regenerative medicine. Candidate: My long-term research goal is to investigate how epigenetic mechanisms impact human health and disease, specifically to understand how epigenetic mechanisms regulate complex tissues. My long-term career goals are to maintain a successful independent research program and educate future scientists. The K99/R00 Pathway to Independence Award will allow me to gain the critical training needed to achieve my long-term research and career goals. I will use experimental data obtained from this proposal as the basis for my own independent research. Training environment: Dr. Haifan Lin (mentor), my advisory committee, and Yale University provide an excellent training program, an intellectually stimulating community, and a well-supported research environment. In this training environment I will gain scientific knowledge, research expertise, grant writing ability, lab management skill, and additional leadership skills. All these will enhance my ability to obtain a tenure-track faculty position and achieve my long-term research and career goals. PUBLIC HEALTH RELEVANCE: The self-renewal and differentiability of stem cells promise great therapeutic potentials in regenerative medicine. This proposal aims to understand the mechanisms regulating gene expression that program stem cell identity by using Drosophila as the model system. This work would reveal fundamental knowledge about stem cell biology, thereby accelerating the use of stem cells in regenerative medicine.

ABSTRACT UTX is a chromatin modifier required for the development of brain, heart, and bone. To facilitate gene activation, UTX removes methylation from methylated lysine 27 in histone H3 (H3K27 methylation) and promotes H3K27 acetylation, H3K4 methylation, and open chromatin structure. In humans, UTX mutations are causally linked to a developmental syndrome and to many childhood and adult cancers of the brain, blood, bladder, esophagus, kidney, and breast. Although the importance of UTX is established, how it targets and regulates genes remains unclear. In particular, contradictory findings raise the question about which chromatin modifying activity of UTX is important for developmental gene regulation in stem cells. This knowledge gap limits our understanding of the etiology of developmental defects and cancers associated with UTX dysfunction or H3K27 modifications. Our long-term goal is to fill this knowledge gap by determining how UTX regulates chromatin structure and gene expression to govern stem cell functions. Our preliminary studies identified a protein network of UTX that is important for the differentiation of human pluripotent stem cells to the neural lineage. In this network, DNA damage response factors play a noncanonical role in regulating gene expression. Our central hypothesis is that this UTX-centric network facilitates chromatin changes and transcriptional activation during stem cell differentiation. To test this hypothesis, we plan to identify the chromatin-regulatory activity of UTX that affects transcription, examine the noncanonical function of DNA damage response factors in this network, and elucidate the role of a downstream effector that executes gene expression programming. Our approaches will take advantage of the conceptual innovation about a new UTX-driven protein network and the technological innovation of combining Cas9-CRISPR for structure?function studies, genomics assays, and the human cortical organoid model. If successful, we expect our findings to have wide implications on epigenetic regulation of human stem cells in development and cancer.