The Payne laboratory focuses on how genetic and epigenetic modulators promote the development and maintenance of adult stem cells.
Current Research Projects
Epigenetics of Stem Cells and the Stem Cell Niche
Microenvironments, or niches, support the maintenance of stem cells and facilitate the development of tumors through largely unknown mechanisms. Cell-autonomous genetic pathways and epigenetic networks have emerged as important determinants for the self-renewal and differentiation of stem cells in embryonic, juvenile, and adult tissues. The importance of non-cell autonomous genetic and epigenetic factors is less well established. Our goal is to identify and characterize the genetic and epigenetic mechanisms utilized by both stem cells and their surrounding niche in supporting the stem cell program. For these studies, the developing mouse testis is used to examine interactions between male germline stem cells (GSCs) and their somatic niche.
Within the testis, differentiated germ cells are continually replenished by self-renewing GSCs to ensure the continuation of spermatogenesis throughout the lifetime of the male. GSCs are adult stem cells that develop after birth but which derive from embryonic primordial germ cells (PGCs). Under abnormal conditions, PGCs are thought to become pluripotent in vivo, develop into carcinoma in situ, and form post-pubertal testicular germ cell tumors, the most common cancer in men aged 15-40. When GSC differentiation occurs at the expense of self-renewal, depletion of germ cells and infertility can result.
Several candidate factors influencing GSC self-renewal and differentiation are being studied: chromatin remodeling gene Sin3a, Polycomb group member Ezh2, and a chemokine ligand and its receptor, Cxcl12 and Cxcr4. Current research is examining the role of Sin3a in somatic Sertoli cells, which support GSCs and nurture all differentiating germ cells. Analysis of Ezh2 in GSCs as well as in testicular germ cell tumors is being conducted to determine whether an altered “Polycomb repression signature” promotes germ cell tumorigenesis. Characterization of Cxcl12, which is expressed in Sertoli cells, and Cxcr4, expressed in germ cells, is being performed to determine whether this chemokine signaling pathway is required to maintain GSCs in their niche and whether this mechanism involves non-coding microRNAs.
To achieve these aims, distinct testicular cell populations are separated by fluorescence- and magnetic-activated cell sorting and analyzed by transcriptional profiling. Potential SIN3A and EZH2 complex-bound target genes are identified by chromatin immunoprecipitation. Loss-of-function effects are examined by one of two methods: generation of conditional knockout mice or RNAi knockdown and transplantation of cultured GSCs into recipient testes. Future studies are aimed at understanding how the niche maintains stem cells and ensures proper organogenesis, with the possibility of tissue regeneration and cancer prevention as therapeutic applications.