Epigenetic gene regulation for stem cell fates

St. Jude Children'S Research Hospital, Memphis TN

Investigators

Abstract

ABSTRACT In stem cells, the interactions among transcription circuitry, extrinsic and intrinsic signaling pathways, and epigenetic modifiers lead to transcriptional outputs that direct different cell fates. These cell fates include self- renewal, cell differentiation, and cell death. These remarkable properties are fundamental to the biology of stem cells and essential for human development, yet our grasp of their workings is relatively scarce. This knowledge deficiency has stark consequences, as the vast majority of human embryos do not complete development. My lab seeks to uncover the epigenetic mechanisms that underlie stem cell fates during embryogenesis. We focus on the key knowledge gap: how histone H3 lysine 27 (H3K2)7 modifiers respond to intrinsic and external cues to dynamically change H3K27 marks, regulate gene expression, and control cell fates. The H3K27 residue and its modifiers are strongly associated with myriad pediatric and adult cancers and developmental disorders. PRC2 and UTX catalyze H3K27 methylation and demethylation, respectively, often to regulate the same chromatin targets. Although PRC2 and UTX are nearly ubiquitous in all cells, their dysregulation causes cell type- and developmental stage-specific defects. Specifically, PRC2 and UTX defects result in opposite phenotypes in cell and tissue growth and neural specification in experimental models and human patients. Therefore, we seek to understand the fundamental mechanisms of PRC2 and UTX in developmental gene regulation and in the long term, translate our knowledge to disease studies. We had identified UTX, PRC2-binder YBX1, UTX-binder 53BP1, and PRC2-binder SNIP1 as key epigenetic regulators of stem cell fates. In research direction 1, we will examine developmental signaling pathways and structural basis that regulate these protein interactions and stem cell fates. As PRC2 is causally associated with pediatric high-grade glioma, we will test UTX and YBX1 for epigenetic dependencies in models of this disease. In research direction 2, we will examine the UTX–53BP1 mechanism at promoters and enhancers and the coordination of PRC2 and UTX–53BP1 activities by the kinase ATM in pluripotent stem cell models. We expect to uncover mechanistic basis of the opposing yet cooperative actions of PRC2 and UTX networks in developmental gene regulation and advance our knowledge about cross-functional factors in transcription and DNA damage response. The extensive research program we propose is based on our established expertise and broad vision. Development and execution of these research directions have continuously benefited from enhancement of diverse perspectives. We expect our results to synergize with each other to reveal epigenetic programs, signaling pathways, and transcription factors that coordinate fundamental stem cell decisions. Our findings will have key implications for human disease, tissue homeostasis, and injury repair.