Sunday, November 24, 2024
11/24/2024
Project Summary Our global objective is to elucidate the mechanisms underlying tissue homeostasis and regeneration in mammalian skin and to understand how this process goes awry in inflammation and cancers. Central to achieving this goal is to determine how stem cells sense and tailor their programs of gene expression in order to perform their particular tasks during homeostasis and wound repair and survive under stressful situations. Past AR31737 research has revealed that adult epidermal and hair follicle (HF) stem cells originate from a common embryonic skin progenitor, but in adult skin, they reside in distinct microenvironments. While maintaining some commonalities, their different niches endow stem cells with distinct molecular properties and instructions to perform separate tasks. Upon injury, the nearest stem cells must respond and adopt a plasticity that enables them to regenerate either epidermis or hair follicles irrespective of the niche from whence they came. We have learned that this `dual lineage' plasticity, transient in a wound state, is hijacked and becomes constitutive in cancer. We've also learned that at the heart of stem cell identity and responsiveness are niche-specific transcription factors (TFs) that act in concert with DNA effectors of environmental signals (e.g. pSMAD1/4 for BMP signaling and LEF1/TCF1 for WNT/β-catenin signaling) to regulate key genes whose expression must rapidly change with the environment. In yrs 39-44 of AR31737 research, we'll now address: What are the chromatin dynamics that enable skin stem cells to choose between epidermal and HF fates? What are the key TFs involved and how do they drive the epigenetics needed to make these fate decisions? How do HF stem cells maintain their fate during homeostasis? How do these stem cells enter a plastic state following injury and then change their identity to epidermal stem cells when they find themselves in the epidermis after repair is complete? Finally, we have discovered that chromatin remodeling in epidermal stem cells is rapid after injury and other types of inflammatory stimuli, but once tissue homeostasis is restored and inflammation has waned, some of these changes resolve slowly. What are the mechanisms underlying this epigenetic memory, and how does it affect tissue fitness? To answer these questions, we will couple in vivo high throughput technologies with our functional interrogation methods, involving in utero lentiviral delivery of epigenetic reporter genes, inducible genes, RNAis and Crispr/CAS guide RNAs to selectively target the skin's stem cells. At the conclusion of this research, we expect to have advanced our knowledge of tissue homeostasis, wound-repair, inflammatory disorders and malignancies and provided new insights to therapeutic strategies.
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