Our global objective is to elucidate the mechanisms underlying tissue homeostasis and regeneration in mammalian epidermis and its appendages, and to understand how this process goes awry in human skin cancers. A central issue in achieving this goal is to understand how adult skin maintains and transcriptionally regulates a pool of stem cells in the hair follicle (HF-SCs) that drive new growth during the hair cycle and repair the epidermis upon injury. At the start of each new hair cycle, two key signals--Wnts and Bmp inhibitory factors-- converge to stimulate HF-SCs to stabilize 2-catenin and generate proliferative but transient progeny that will then differentiate to make hair. Increasing evidence points to 2-catenin's near universal role in regulating SC proliferation and/or fate determination, and excessive stabilized 2-catenin is frequently seen in human cancers. 2-Catenin acts as a co-factor for the Lef1/Tcf family of DNA binding proteins. In HF-SCs, two family members-- Tcf3 and Tcf4--are co-expressed, where they function redundantly to repress differentiation in the absence of Wnt signaling and promote proliferation and fate commitment in its presence. Interestingly, in cultured embryonic stem cells (ESCs), Tcf3 is an integral component of the pluripotency regulatory complex (Sox2, Oct4, Nanog), not present in adult SCs. How Wnts/2-catenin regulate Tcfs to affect the transcriptional machinery and whether they function as a universal rheostat in controlling key SC genes remains unknown. The hair follicle offers a particularly attractive model for addressing this important issue, as it provides an especially abundant source of SCs which express Tcf3 and respond in a temporal and spatial manner to stabilized 2-catenin. Recent advances in chromatin immunoprecipitation, deep sequencing and HF-SC isolation and purification now make it possible to define the global transcriptional and epigenetic changes in Tcf/Lef-regulated genes that occur when HF-SCs in vivo receive a Wnt signal, and become activated to exit their native niche and progress along a specified lineage. Moreover, with the recent identification of Lhx2, Nfatc1 and Sox9 as additional essential HF-SC transcription factors, global chromatin mapping should illuminate how this transcriptional machinery governs HF-SC behavior and how external stimuli change the chromatin states of key target genes. We've devised strategies to do this and to decipher which direct target genes are most likely relevant to the critical features of stem cell behavior, activation and lineage commitment. Finally, we've developed innovative methodology to rapidly assay the functional significance of our candidates by lentiviral mediated knockdown in HF-SCs in vitro, and in cycling postnatal HFs and development in vivo. By dissecting how these signaling pathways operate to transcriptionally balance stem cell activation, proliferation and differentiation in hair follicle, new targets are likely to emerge for the development of new pharmaceutical agents that can inhibit Wnt signaling and uncontrolled growth in cancers.
Wnt signaling plays a central role in development and in regulating the properties of stem cells. This research focuses on deciphering the key target genes that change in hair follicle stem cells as they receive signals from their surroundings, begin to proliferate and generate new hair growth. Gone awry, these mechanisms lead to skin cancers. By unearthing the direct genes and mechanisms involved in normal stem cell activation, we are likely to uncover new targets for the development of anti-cancer therapeutics.
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