The role of epigenetic regulators in epidermal stem cell control
Stem cells are unique cells within a body. They are characterized by the ability to renew themselves and to differentiate into a diverse range of specialized cell types. Although most organs and tissues have been shown to contain stem cells, skin is probably one of the most suitable mammalian systems to study stem cells.
Skin is the outermost barrier between body and environment that protects a body against infection and dehydration. During development skin and its lineages, which include the epidermis, hair follicles, and sebaceous glands, originate from a single layer of embryonic skin stem cells. Postnatally separate pools of adult stem cells that are present in hair follicles and the epidermis maintain skin during normal homeostasis and upon wounding (Figure 1). The availability of genetic tools to perform in vivo loss- and gain-of function studies, the existence of molecular markers of stem cells and their differentiated progenies, as well as the possibility to purify and to culture stem cells makes skin a unique model system to study stem cells.
Identification of molecular mechanisms that control the self-renewal and differentiation of stem cells is fundamentally important to understand tissue development and homeostasis as well as the progression of various tissue disorders including cancer. Increasing number of evidence has pointed to the importance of epigenetic regulators in control of these processes. Our long-term interest is to elucidate the roles of epigenetics regulators in stem cell control using skin as a model system. We are interested: 1) to uncover whether the epigenetic machinery controls cell fate; 2) to understand how functions of epigenetic regulators in stem cell control differ between pluripotent embryonic stem cells and unipotent skin stem cells; and 3) to elucidate how changes in functions of epigenetic regulators lead to diseases and cancer.
Polycomb complex in stem cell control
Our recent studies have shown that a chromatin repressor called the Polycomb complex plays an important role in control of skin stem cells. We have shown that the Polycomb complex controls proliferative potential of skin stem cells by repressing the Ink4A-Arf-Ink4B gene locus and tempers the developmental rate of differentiation by preventing premature recruitment of transcriptional activators to promoters of genes that are required for skin differentiation (Figure 2).
In the lab we continue addressing the role of the Polycomb complex in stem cell control. We are interested to understand how the Polycomb complex is recruited to differentiation genes in stem cells and how it is realized upon induction of differentiation. We study molecular mechanisms by which the Polycomb complex represses gene expression. Finally we are interested to uncover whether alterations in the Polycomb activity lead to skin diseases and cancer.
Epigenetic regulators in stem cell control
Our studies have also revealed differential expression of other important epigenetic regulators between embryonic skin stem cells and differentiated cells, suggesting an important role for epigenetic regulation in the control of skin stem cells. Specifically we found that embryonic skin stem cells express histone methyltransferases, histone demethylase, histone acetyltransferases and DNA methyltranferases. Some of these epigenetic regulators have been implicated in the control of pluripotent embryonic stem cells; however, their roles in tissue development and regulation of tissue-specific stem cell have not yet been addressed. To characterize the epigenetic regulatory network, the roles of the epigenetic factors in the control of skin development will be examined.
Figure 1. The skin and its appendages.
Figure 2. A Role for the Polycomb complex in Regulating Temporal Differentiation and Epidermal Barrier Acquisition during Skin Development
(A–B) Histological and immunofluorescence microscopy reveals accelerated epidermal differentiation in E16 Ezh2 cKO epidermis. Semithin section in (A) are toluidine blue stained. Frozen sections in (B) are labeled with Abs as indicated (color coding according to secondary Abs).
(C) Blue dye exclusion assay to measure skin barrier shows premature barrier formation in E16 Ezh2cKO animals.
(D) Differential expression of Polycomb complex proteins and Ap1 activator ensures spatial and temporal program of epidermal differentiation. In WT basal cells, the presence of triM3K27-H3 mark prevents AP1 from binding and activation of late differentiation genes. In Ezh2cKO or in differentiated WT cells, loss of triMeK27-H3 mark allows Ap1 to bind and activate transcription of late differentiation genes.