Hair follicle stem cells (HFSCs) have the unique ability to generate new hair follicles throughout the lifetime of an organism. When the growth of a new hair follicle occurs, HFSCs are activated; they proliferate to fuel the production of a new follicle and quickly return to quiescence. While the means by which this transition between quiescence and activation is regulated remain elusive, identification of these processes is critical, because abnormal HFSC activation has implications in hair loss, aging, and cancer. Polycomb repressive complexes (PRC) 1 and 2 are chromatin transcriptional regulators that are essential for maintaining stem cell identity. By performing loss-of-function studies, we showed that loss of PRC1 in HFSCs results in premature activation of HFSCs and the induction of hair growth, whereas loss of PRC2 leads to a prolonged HFSC quiescence and delayed hair growth. These data show the critical and opposing roles of Polycomb complexes in regulation of HFSC quiescence. This is an intriguing observation because PRC1 and PRC2 are thought to act together, and, in most systems, the loss of either PRC1 or PRC2 results in identical phenotypes. We hypothesize that PRC1 and PRC2 maintain the delicate balance of quiescence and activation, but their mechanism of action is different than what was previously reported.
In Aim 1, we will determine the molecular mechanisms by which PRC2 fine-tunes HFSC quiescence. By performing RNA-seq, we identified that Wnt inhibitors Notum and Sfrp2, and BMP receptor Bmpr1b are upregulated in the PRC2-null HFSC. Because Wnt inhibition and Bmp activation are known to promote HFSC quiescence, we hypothesize that expression of these genes leads to delayed HFSC activation. Here, we will analyze whether expression of Notum, Sfrp2, and/or Bmpr1b promotes HFSC quiescence and recapitulates the PRC2-null phenotype.
In Aim 2, we will examine cooperation between repressive PRC1 and PRC2 functions in control of HFSCs. Our recent studies showed that PRC1 and PRC2 have additive gene-repressive roles and that only loss of both leads to complete de-repression of PRC1/2 target genes. Here, we will ablate repressive functions of both PRC1 and PRC2 complexes in HFSCs, analyze the phenotype, and determine molecular mechanisms of PRC1/2 control of HFSCs.
In Aim 3, we will examine noncanonical gene-activating roles of PRC1 in promoting HFSC quiescence. Because loss of PRC1 and PRC2 show opposing phenotypes, respectively, we hypothesize that PRC1 functions independently of PRC2 to promote the expression of genes that influence HFSC quiescence. Here, we will identify genes that are under the control of PRC1 in HFSCs by performing RNA-seq and ChIP-seq studies and test whether downregulation of said genes results in precocious HFSC activation. The completion of these studies will define how Polycomb-mediated gene regulation fine-tunes the delicate balance between quiescence and activation in HFSCs.
Hair follicle stem cells (HFSCs) are multipotent epithelial stem cells that fuel the production of hair follicles throughout the life of an organism. We have recently identified that the key chromatin regulator, the Polycomb complex, not only plays a critical role in HFSCs but also exerts its function via a novel mechanism of gene regulation. By dissecting the molecular mechanisms of Polycomb-mediated regulation of HFSCs, we aim to gain insight into the regulation of HFSC during normal homeostasis as well as uncover processes that go awry in human diseases such as cancer.
| Cohen, Idan; Zhao, Dejian; Bar, Carmit et al. (2018) PRC1 Fine-tunes Gene Repression and Activation to Safeguard Skin Development and Stem Cell Specification. Cell Stem Cell 22:726-739.e7 |
| Perdigoto, Carolina N; Dauber, Katherine L; Bar, Carmit et al. (2016) Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development. PLoS Genet 12:e1006151 |
| Chen, Ye-Guang; Ezhkova, Elena; Ostankovitch, Marina (2016) Molecular Mechanisms Regulating Stem Cells Fate. J Mol Biol 428:1407-8 |
| Dauber, Katherine L; Perdigoto, Carolina N; Valdes, Victor J et al. (2016) Dissecting the Roles of Polycomb Repressive Complex 2 Subunits in the Control of Skin Development. J Invest Dermatol 136:1647-1655 |
