Transcriptional regulation in normal and diseased epithelia
The long-term goal of the Andersen laboratory is to understand transcriptional control mechanisms that underlie normal development of epidermis, hair follicles and mammary glands, and to use this knowledge to gain insights into carcinogenesis in epithelial tissues.
A major focus of the Andersen laboratory involves investigating the roles of Clim/Nli/Ldb co-activators in stratified epithelia and mammary glands. The Clim proteins were discovered based on their ability to bind to LIM domains of LIM homeodomain factors and confer transcriptional activation by this class of DNA-binding proteins. One member of this family of co-activators, Clim2, is highly expressed in epithelial cells of the epidermis and internal epithelial linings. We have found that Clims interacts with the LIM only protein, LMO4, which is expressed in an overlapping manner in epithelial tissues. Using genetic mouse models we have shown that the Clims are important for maintenance of hair follicle stem cells and cornea homeostasis. In hair follicle stem cells, Clim2 acts in a transcriptional complex with the LIM homeodomain factor Lhx2.
In addition, we have found that the LMO4 gene plays important roles in lobuloalveolar development of the mammary gland. Mice with mammary gland-specific deletion of the LMO4 gene show delayed mammary gland development due to decreased mammary epithelial cell proliferation. This is consistent with common upregulation of LMO4 in human breast cancer. Our molecular studies suggest that LMO4 can modulate activity of the TGFbeta/BMP pathways, and affect proliferation of mammary epithelial cells.
Another major focus of our laboratory has been elucidating the role of Grainyhead-like transcription factor Get1/Grhl3. We have discovered that this gene whose function is conserved throughout evolution of multicellular organisms promotes differentiation of epidermal keratinocytes and also promotes keratinocytes migration. Recently, we also discovered that Get1/Grhl3 is critical for bladder epithelial cell differentiation. The Grainyhead genes seem to have a key function in epithelial repair and barrier formation, and we are currently pursuing the molecular mechanisms underlying this feature.
Accumulating evidence suggest that the hair follicle plays important roles in skin carcinogenesis. Some epidermal cancers, especially basal cell carcinoma, may originate from hair follicle cells. In addition, subversion of normal regulators of hair morphogenesis, such as the Wnt and hedgehog pathways, is responsible for skin cancer. We recently found that circadian clock genes affect hair follicle growth and cycling, apparently by regulation the expression of cell cycle regulators.
Andersen, B., Hariri, A., Pittelkow, M.R., & Rosenfeld, M.G. 1997. Characterization of Skn-1a/i POU domain factors and linkage to papillomavirus gene expression. J. Biol. Chem. 272:15905-15913.
Bach, I., Carriere, C., Ostendorff, H.P., Andersen, B., & Rosenfeld, M.G. 1997. A family of LIM domain associated cofactors confer transcriptional synergism between LIM- and Otx homeodomain proteins. Genes & Dev. 11:1370-1380.
Andersen, B., Weinberg, W.C., Rennekampff, O., McEvilly, R., Bermingham, J.R., Hooshmand, F., Vasilyev, V., Hansbrough, J.F., Pittelkow, M.R., Yuspa, S.H., & Rosenfeld, M.G. 1997. Functions of the POU domain genes Skn-1a/i and Tst-1/Oct-6/SCIP in epidermal differentiation. Genes & Dev. 11:1873-1885.
Sugihara, T.M., Bach, I., Kioussi, C., Rosenfeld, M.G. & Andersen, B. 1998. Mouse Deformed epidermal autoregulatory factor 1 recruits a LIM domain factor, LMO-4, and CLIM coregulators. Proc. Natl. Acad. Sci. 95:15418-15423.
Bach, I., Rodriguez-Esteban, C., Carriere, C., Bhushan, A., Krones, A., Rose, D.W., Glass, C.K., Andersen, B., Belmonte, J.C.I. & Rosenfeld, M.G. 1999. RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nature Genetics 22:394-399.
Sugihara, T.M., Kudryavtseva, E., Kumar, V., Horridge, J.J. & Andersen, B. 2001. The POU domain factor Skin-1a represses the keratin 14 promoter independent tof DNA binding: possible role for interactions between Skn-1a and CBP/p300. J. Biol.Chem. 276:33036-33044.
Kudryavtseva, E., Sugihara, T.M., Wang, N., Lasso, R., Gudnason, J.F., Lipkin, S.M. & Andersen, B. 2003. Identification and characterization of a novel LMO-4-interacting protein, mammalian Grainyhead-like Epithelial Transactivator (GET-1). Dev Dynamics 226:604-17.
Wang, N., Kudryavtseva, E. Ch'en, I.L., McCormick, J., Sugihara, T.M., Ruiz, R. & Andersen, B. 2004. Expression of an engrailed-LM04 fusion protein in mammary epithelial cells inhibits mammary gland development in mice. Oncogene. 23:1507-1513.
Lin, K.K., Chudova, D., Hatfield, G.W., Smyth, P. & Andersen, B. 2004. Identification of hair cycle-associated genes from time-course gene expression profile data using replicate variance. Proc Natl Acad Sci. 101:15955-15960.
Lu, Z., Lam, K.-S., Xu, X., Wang, N. & Andersen, B. 2006. LMO4 can interact with Smad proteins and modulate Transforming Growth Factor-β signaling in epithelial cells. Oncogene, 25:2920-2930.
Yu, Z., Lin, K.K., Bhandari, A., Spencer, J.A., Xu, X., Wang, N., Lu, Z., Gill, G.N., Roop, D.R., Wertz, P. & Andersen, B. 2006. The Grainyhead-like Epithelial Transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4. Developmental Biology, 299:122-136.
Wang, N., Lu, Z., Lin, K.K., Lam, K.S., Newton, R., Xu, X., Yu, Z., Gill, G.N. & Andersen, B. 2007. The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells. Oncogene 26:6431-6441.
Xu, X., Mannik, J., Kudryavtseva, E., Lin, K.K., Flanigan, L.A., Spencer, J., Soto, A., Wang, N., Lu, Z., Yu, Z., Monuki, E.S. & Andersen, B. 2007. Co-factors of LIM domains (Clims/Ldb/Nli) regulate corneal homeostasis and maintenance of hair follicle stem cells. Developmental Biology 312:484-500.
Yu, Z., Bhandari, A., Mannik, J., Pham, T., Xu, X. & Andersen, B. 2008. Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure. Developmental Biology 319:56-67.
Yu, Z., Mannik, J., Soto, A., Lin, K.K. & Andersen, B. 2009. The epidermal differentiation-associated factor Grainyhead-like factor Get1/Grhl3 is also involved in urothelial differentiation. EMBO J. 28:1890-1903.
Lin, K.K., Kumar, V., Geyfman, M., Chudova, D., Ihler, A.T., Smyth, P., Paus, R., Takahashi, J.S. & Andersen, B. 2009. Circadian clock genes contribute to the regulation of hair follicle cycling. PLOS Genetics. 5(7):e1000573.