論文紹介著者

Ophelia Veraitch（博士課程　1年）
GCOE　RA
皮膚科学

第一著者名・掲載雑誌・号・掲載年月

Lien WH／Cell Stem Cell 9, 219-232. 2011

文献の英文表記：著者名・論文の表題・雑誌名・巻・号・ページ・発行年（西暦）

Lien WH, Guo X, Polak L, Lawton LN, Young RA, Zheng D and Fuchs E. Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell 9, 219-232. 2011

論文解説

Hair follicles undergo successive cycles of growth (anagen), regression (catagen) and rest (telogen). This unique cycling depends on the epithelial stem cells that reside in the outer root sheath of the hair follicle, known as the bulge (Cotsarelis et al. 1990). Bulge cells are generally quiescent but transiently proliferate at the onset of anagen. Activated bulge cells progeny then surround the hair follicle dermal papilla to form a matrix that goes on to form the hair shaft and surrounding inner root sheath. However, exact mechanisms that govern bulge cells cycling through quiescent and activated states is currently unclear. Lien et al. set out to investigate if these changes occur at a transcriptional level or if epigenetic mechanisms impact hair follicle stem cell behavior and lineage determination.

Quiescent bulge, activated bulge and anagen matrix cells were isolated by fluorescence-activated cell sorting (FACS) by using previously known markers. Initially, molecular signatures collated from microarray analyses gave a clearer picture of changes in mRNA expression that occurs during the cycling of quiescent bulge to anagen bulge to transit amplifying matrix cell states. Quiescent bulge cells were enriched for balancers of cell survival, apoptosis and negative regulators of gene expression. Activated bulge signatures favored cell migration and proliferation genes, and the matrix cells were most highly enriched for cell cycle enhancers as well as hair follicle lineage markers like Lef1 and Msx1. To further investigate these changes is mRNA the authors investigated the epigenetic changes that occur during the transitional states in the hair cycle.

Increasing evidence is revealing the importance of histone modifications in affecting transcription factor accessibility and chromatin structure, especially in stem cell populations. Among these, H3K4me3 is associated with transcriptional initiation and H3K27me3 marks genes that have low transcriptional activity. Genome wide mapping of histone methylation sites in cultured human and mice embryonic stem cells have shown that genes marked by both H3K4me3 and H3K27me3 display "bivalent" genes. This has led to the interpretation that bivalency marks populations that are poised for subsequent transcription or repression (Hong et al. 2011; Fisher and Fisher, 2011). By adopting the methods of chromatin immunoprecipitation and deep sequencing (CHIP-seq) genome wide profiles of the H3K4me3 and H3K27me3 marks in the bulge populations authors revealed that the isolated quiescent bulge cells in vivo displayed very few bivalent genes, in a marked contrast to cultured embryonic stem cells. The lack of bivalency in this population could explain how activated bulge cells can return to quiescence mid-anagen, the developmentally restricted nature of bulge cells and the inability of bulge cells to contribute to the interfollicular epidermis in wounding. On further analysis of the chromatin mapping studies novel signaling factors that may regulate bulge cells namely Gremlin1, GDF10, Activin B and follistatin were proposed. However, further in vivo functional analysis of these factors is needed to further elucidate the role of these factors in hair follicle cycling.

Previously, relatively little was known on the epigenetic factors that govern the complex process of bulge stem cell activation and quiescence during the hair cycle. By isolation of the different states of bulge cells and ultilisation of the powerful tool of chromatin state mapping significant advances in unfolding the epigenetic factors that govern this process made been made.