Ph.D., University of Chicago, Chicago, Illinois, 1995
Skin and mammary stem cells, Wnt signaling, chromatin, transcription
The development, maintenance, and regeneration of complex mammalian tissues involve multi-tiered control mechanisms including those regulating commitment to different cell lineages and self-renewal/proliferation/differentiation along a particular lineage. Regenerative tissues such as skin and mammary gland are excellent model systems to study the genetic pathways underlying such control mechanisms, as they contain stem cells that persist throughout the life span of an animal and possess self-renewal and differentiation potential. Our long-term goal is to understand the transcriptional and chromatin control of epithelial stem cell self-renewal and differentiation, and to gain insights into how mis-regulation can result in diseased conditions including skin and breast cancer.
We study two families of transcription/chromatin regulators, namely Ovol zinc finger proteins and Pygopus PHD finger proteins using a combinatory approach involving mouse genetics, developmental biology, biochemistry, molecular biology, and cell biology. Work from us as well as others has shown that these proteins are either regulated by, or directly participate in, important developmental signaling pathways such as Wnt-beta-catenin-LEF/TCF and TGFbeta/BMP, and act at least in part through regulating gene transcription and histone modifications.
Ovol proteins - We have shown using knockout mouse and cell culture models that Ovol1 is required for developmental epithelial progenitor cells to exit proliferation so they can terminally differentiate. Our molecular analysis has shown that it does so by recruiting histone deacetylases and regulating key cell cycle genes including c-Myc and Id2. Our current research addresses the function of Ovol2 in skin and mammary epithelial stem cell development and differentiation, as well as how it performs its function at a molecular level.
Pygopus proteins - We have shown that Pygopus 2 (Pygo2) converges with Wnt signaling to regulate multiple developmental processes including that of skin hair follicle and mammary gland. We have uncovered a critical role for Pygo2 in regulating the expansion of mammary epithelial stem/progenitor cells, via "reading" and "writing" histone H3 K4 trimethylation, a specific type of histone code that is associated with active chromatin. Our current studies focus on the identification of Pygo2 targets and interacting proteins, as well as on the involvement of Pygo2 in breast tumorigenesis.
Glucksmann-Kuis, M. A., Dai, X., Markiewicz, P., and Rothman-Denes, L. B. (1996). "E. coli SSB activation of N4 virion RNA polymerase: specific activation of an essential DNA hairpin required for promoter recognition". Cell 84, 147-154.
Dai, X. and Rothman-Denes, L. B. (1998). "Sequence and DNA strucutral determinants of N4 virion RNA polymerase-promoter recognition". Genes & Development 12, 2782-2790.
Dai, X., Schonbaum, C., Degenstein, L., Bai, W., Mahowald, A., Fuchs, E. (1998). "The ovo gene required for cutcle formation and oogenesis in flies is involved in hair formation and spermatogenesis in mice". Genes & Development 12, 3452-3463.
Li, B., Mackay, D. R., Dai, Q., Li, T. W. H., Nair, M., Fallahi, M., Schonbaum, C., Fantes, J., Mahowald, A., Waterman, M. L., Fuchs, E., and Dai, X. (2002). The LEF1/b-catenin complex activates movo1, a mouse homolog of Drosophila ovo gene required for epidermal appendage differentiation. Proc. Natl. Acad. Sci. USA 99, 6064-6069.
Nair, M., Teng, A., Bilanchone, V., Agrawal, A., Li, B. and Dai, X. (2006). Ovol1 controls the growth arrest of embryonic epidermal progenitor cells and represses c-Myc transcription. J. Cell Biology 173, 253-264.
Gu, B., Sun, P., Yuan, Y., Moraes, R., Li, A., Teng A., Agrawal, A., Rhéaume, C., Bilanchone, B., Veltmaat J. M, Takemaru, K., Millar, S. Lee, E. Y-H. P., Lewis, M. T., Li, B., and Dai, X. (2009). Pygo2 expands mammary progenitor cells by regulating histone H3 K4 methylation. J. Cell Biology 185:811-26. News and Commentary.
Watanabe, K. and Dai, X. (2011). Winning Wnt: race to Wnt signaling inhibitors. Proc. Natl. Acad. Sci. USA. 108(15):5929-30.
Watanabe, K. and Dai, X. (2011). A Wnter revisit: new faces of beta-catenin and TEFs in pluripotency. Sci. Signaling. Oct 4;4(193):pe41. PMCID – In process.
Watanabe, K. Fallahi, M. and Dai, X. (2013). Chromatin effector Pygo2 regulates mammary tumor initiation and heterogeneity in MMTV-Wnt1 mice. Oncogene. Jan 21.
Gu, B., Sun, P., and Dai, X. Chromatin Effector Pygo2 Mediates Wnt-Notch Cross-talk to Suppress Luminal/Alveolar Potential of Mammary Stem and Basal Cells. Cell Stem Cell 13(1):48-61.