Our current research projects include:

1: Determining the mechanisms that underlie the formation and maintenance of hairy versus hairless skin and regulate hair patterning.

Different regions of mammalian skin vary in their functions, regenerative properties, and responses to injury and disease. Delineating the mechanisms that establish and maintain skin heterogeneity has potential to reveal improved therapeutic strategies. Positional information resides in the skin dermis, but the responsible molecular signals are poorly defined. We are using regional variation of hair follicle development and regeneration as a model system to address this question. We are particularly focusing on endogenous Wnt inhibitors as mediators of regional variation and hair patterning in the skin; our initial studies have identified the Dickkopf2 (DKK2) inhibitor as playing a critical role in permitting development of hairless plantar skin. Current directions include using unbiased single cell multiomics approaches to reveal additional secreted inhibitors that direct regional skin variation in developing mouse and human skin; identifying candidate enhancer regions and transcription factors that specify regional skin identity; and understanding the evolutionary mechanisms underlying the diversity of regional skin phenotypes among mammalian species.

2: Mechanisms controlling Meibomian gland homeostasis and aging.

Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. In published work, we usedsnRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in micetoidentify markers for stem cell populations that maintain distinct regions of the gland.WeidentifiedHedgehog (Hh) signaling as a key regulator of stem cell proliferation. Consistent with this, we showedthat human Meibomian gland carcinoma exhibits increased Hh signaling. In aging, we found that Meibomianglands display decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.In current work, we are investigating the functions of epigenetic regulators, including the histone deacetylases HDAC1, HDAC2, and HDAC3 in homeostasis and aging of Meibomian glands. We are also extending these analyses to other skin glands, including sweat glands which show altered structure and function in aging, to understand whether age-associated gland dysfunction involves common mechanisms across different types of glands.

3: Identifying pioneer transcription factors that control development and stem cell activity in skin and oral epithelia.

Regenerative processes in skin and oral epithelia require cross-talk of multiple cell signaling and epigenetic mechanisms; failure of this communication leads to a range of diseases from skin cancers to hair loss conditions. Delineating how these inputs are coordinated to impact gene expression at the level of chromatin has potential to identify novel therapies for skin dysfunction. Pioneer transcription factors initiate gene expression by binding nucleosome-enriched silent chromatin and recruiting chromatin modifiers to provide access for transcription machinery. Key regulatory genes in hair follicle stem cells are associated with “super enhancers” containing binding sites for multiple transcription factors, suggesting that transcription factors activated in response to diverse signals collaborate with each other and with chromatin modifiers to coordinate cell-type specific transcriptional output. We are using genetic mouse models to investigate the roles of several families of putative pioneer transcription factors in controlling skin and oral stem cell proliferation and differentiation.