Changes in chromatin structure, such as post-translational modifications of histones or DNA methylation, have a profound effect on gene expression by either facilitating or restricting the access of transcription factors to DNA. These epigenetic modifications dynamically change during cell commitment to orchestrate cell differentiation. The Polycomb Repressor Complex (PRC) is a key epigenetic repressor that is targeted to specific sets of genes associated with the differentiation state of the cell. However, the majority of Polycomb proteins do not have DNA-binding domains, and one of the biggest challenges in epigenetics is to define how PRC is specifically directed to target genes. The focus of Dr. Ezhkova's lab is to explore the question of how epigenetic marks are established to influence cell fate. To this end, I will focus on skin stem cell differentiation, in particular, how the PRC is targeted to skin genes and how PRC-repression is removed upon cell commitment. I will explore the interactions between PRC, DNA binding proteins, and long non-coding RNAs, to determine how these interactions modulate PRC activity. I will use in vivo strategies and live-cell imaging approaches to study PRC targeting during skin development. To assess how PRC operates to prevent cell differentiation of embryonic epidermal progenitors, I will explore its interaction with other chromatin repressors, as well as transcriptional activators. These studies will elucidate the interplay that establishes epigenetic memory of the skin stem cell state, which will shed light on skin diseases such as cancer, and will be important for development of stem-cell-based therapies.