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 and other diseases in epithelial tissues.
Currently, the Andersen laboratory is pursuing two lines of investigations into epidermal biology.
First, our laboratory has been elucidating the role of Grainyhead-like transcription factor Get1/Grhl3 in epidermal differentiation and repair. We discovered that Grhl3, whose function is conserved throughout evolution of multicellular organisms, promotes differentiation of epidermal keratinocytes and keratinocyte migration through activation of multiple genes. We also discovered that Grhl3 is critical for bladder epithelial cell differentiation; in this case trough activation of a different set of genes than in the epidermis. This ability of Grhl3 to activate distinct gene sets in different epithelia has led to our interest in epigenetics and chromatin regulation, which we believe constrains the ability of Grhl3 to activate genes in a cell type-specific manner. As part of this work, we recently found that Grhl3 recruits histone methyl transferases of the Trithorax group to activate gene expression.
Second, our laboratory has been elucidating the role of the circadian clock in skin. We found that the clock is involved in regulation of the hair follicle growth cycle and more recently we showed that the core clock gene Bmal1 is required for the striking circadian variation in epidermal progenitor cell proliferation. Furthermore, we have shown that the sensitivity to UVB-induced DNA damage in the skin is time of day dependent and regulated by the circadian clock. Our findings suggest that the circadian clock coordinates metabolism and the cell cycle in stem/progenitor cells of the epidermis, presumably protecting stem cells from ROS-mediated DNA damage.
Our work on the mammary gland has focused on the role of Clim/Nli/Ldb co-activators and associated LIM domain proteins. Using genetic mouse models we have shown that that a complex of LMO4 and Clim2 is important for mammary gland development. Current studies focus on the potential role of this complex in breast cancer.
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.
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.
Verma S, Salmans ML, Geyfman M, Wang H, Yu Z, Lu Z, Zhao F, Lipkin SM, Andersen B. 2012. The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development. Developmental Biology 369:249-60.
Hopkin AS, Gordon W, Klein RH, Espitia F, Daily K, Zeller M, Baldi P, Andersen B. 2012. GRHL3/GET1 and trithorax group members collaborate to activate the epidermal progenitor differentiation program. PLOS Genetics 8(7):e1002829.
Geyfman M, Kumar V, Liu Q, Ruiz R, Gordon W, Espitia F, Cam E, Millar SE, Smyth P, Ihler A, Takahashi JS, Andersen B. 2012. Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. Proc Natl Acad Sci. 109:11758-63.
Bhandari A, Gordon W, Dizon D, Hopkin AS, Gordon E, Yu Z, Andersen B. 2013. The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1. Oncogene. 32:1497-507.