Transcriptional regulation in normal and diseased epithelia
The long-term goal of the Andersen laboratory is to understand the transcriptional control mechanisms that underlie normal development of epithelia such as the epidermis, the cornea and the mammary glands, and to use this knowledge to gain insights into diseases of epithelial tissues.
A major focus of the work has been elucidating the role of Grainyhead-like transcription factor Get1/Grhl3 in epidermal differentiation and repair. We discovered that this factor promotes both differentiation and migration of epidermal keratinocytes through the activation of large gene expression programs. In more recent studies, we demonstrated a role for Grhl3 in the repair of epidermal injury, including that found in immune-mediated injury such as the skin disease psoriasis. We also discovered that Grhl3 is critical for bladder epithelial cell differentiation where it activates distinct gene expression program. We are now using genomics approaches to investigate how Grhl3 interacts with epigenetic regulators to control gene expression programs in epidermal keratinocytes. This work has implications for understanding common skin diseases, including wound healing, psoriasis and skin cancer.
A second major focus of the laboratory is to understand the role of the circadian clock in skin biology. We initially became interested in the role of the circadian clock through our work on the hair growth cycle. These early studies revealed that the circadian clock affects hair follicle growth and cycling, apparently through regulation the expression of cell cycle regulators. In subsequent work, we found that the circadian clock is required for diurnal variation in epidermal stem cell proliferation and confers diurnal changes in the susceptibility to UVB-induced DNA damage, the major causative agent of skin cancer. Most recently, we demonstrated that the circadian clock coordinates intermediary metabolism with cell cycle stages in epidermal stem cells. This work has implications for understanding skin cancer and skin aging.
A third focus has been on 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, conferring transcriptional activation by associating with 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 other epithelia. We 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 both hair follicle and mammary gland stem cells, and for cornea homeostasis.
Klein RH, Hu W, Kashgari G, Lin Z, Nguyen T, Doan M, Andersen B. 2017. Characterization of enhancers and the role of the transcription factor KLF7 in regulating corneal epithelial differentiation. J Biol Chem. Sep 15. pii:jbc.M117.793117. doi:10.1074/jbc.M117.793117. [Epub ahead of print]
Wang H, van Spyk E, Liu Q, Geyfman M, Salmans ML, Kumar V, Ihler A, Li N, Takahashi JS, Andersen B. 2017. Time-Restricted Feeding Shifts the Skin Circadian Clock and Alters UVB-Induced DNA Damage. Cell Reports, 20:1061-1072.
Klein RH, Lin Z, Hopkin AS, Gordon W, Tsoi LC, Liang Y, Gudjonsson JE, Andersen B. 2017. GRHL3 binding and enhancers rearrange as epidermal keratinocytes transition between functional states. PLoS Genet. Apr 26;13(4):e1006745.
Klein RH, Stephens DN, Ho H, Chen JK, Salmans ML, Wang W, Yu Z, Andersen B. 2016. Cofactors of LIM Domains Associate with Estrogen Receptor a to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function. J Biol Chem. 291:13271-1385.
Stringari C, Wang H, Geyfman M, Crosignani V, Kumar V, Takahashi JS, Andersen B, Gratton E. 2015. In vivo single cell detection of metabolic oscillations in stem cells. Cell Reports, 10:1-7.
Gordon W, Zeller MD, Herndon-Klein R, Swindell WR, Ho H, Espitia F, Gudjonsson JE, Baldi PF, Andersen B. 2014. A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia. J Clin Invest, 124(12):5205-5218.
Salmans ML, Yu Z, Watanabe K, Cam E, Sun P, Smyth P, Dai X, Andersen B. 2014. The Co-factor of LIM domains (CLIM/LDB/NLI) regulate FGFR2 to maintain basal mammary epithelial stem cells and promote breast cancer initiation. PLOS Genetics, Jul 31;10(7):e1004520.
Stephens D, Herndon-Klein R, Salmans M, Ho H, Gordon W, Andersen B. 2013. The Ets transcription factor EHF as a regulator of cornea epithelial cell identity. J. Biol. Chem. 288: 34304-34324.
Bhandari A, Gordon W, Dizon D, Hopkin A, Gordon E, Yu Z, and 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(12):1497-507.
Geyfman M, Kumar V, Liu Q, Ruiz R, Gordon W, Espitia F, Cam E, Millar SE, Smyth P, Ihler A, Takahashi J, and 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(29):11758-63.
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 lobuloalveolar development. Developmental Biology 369:249-260.
Soto-Hopkin A, Gordon W, Herndon-Klein R, Espitia F, Daily K, Zeller M, Baldi P, and Andersen B. 2012. GRHL3/GET1 and Trithorax Group Members Collaborate to Activate the Epidermal Progenitor Differentiation Program. PLOS Genetics Jul;8(7):e1002829.
Geyfman M, Gordon W, Paus R and Andersen B. 2012. Identification of novel telogen markers underscores that telogen is far from a quiescent hair cycle phase. J. Invest. Derm., 132:721-724.
Lin KK, Kumar V, Geyfman M, Chudova D, Ihler AT, Smyth P, Paus R, Takahashi JS, and Andersen B. 2009. Circadian clock genes contribute to the regulation of hair follicle cycling. PLOS Genetics. 5(7):e1000573.
Yu Z, Mannik J, Soto A, Lin KK., and Andersen B. 2009. The epidermal differentiation-associated factor Grainyhead-like factor Get1/Grhl3 is also involved in urothelial differentiation. EMBO J. 28:1890-1903.
Yu Z, Bhandari A, Mannik J, Pham T, Xu X, and Andersen B. 2008. Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure. Developmental Biology 319:56-67.
Xu X, Mannik J, Kudryavtseva E, Lin KK, Flanigan LA, Spencer J, Soto, A, Wang N, Lu Z, Yu Z, Monuki ES, and 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.
Wang N, Lu Z, Lin KK, Lam KS, Newton R, Xu X, Yu Z, Gill GN and 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.
Yu Z, Lin KK, Bhandari A, Spencer JA, Xu X, Wang N, Lu Z, Gill GN, Roop DR, Wertz P and 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.
Lu Z, Lam K-S, Xu X, Wang N, Andersen B. 2006. LMO4 can interact with Smad proteins and modulate Transforming Growth Factor-? signaling in epithelial cells. Oncogene, 25: 2920-2930.
Lin KK, Chudova D, Hatfield GW, 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.
Wang, N., Kudryavtseva, E., Ch'en, I.L., McCormick, J., Sugihara, T.M., Ruiz, R. & Andersen, B. 2004. Expression of an engrailed-LMO4 fusion protein in mammary epithelial cells inhibits mammary gland development in mice. Oncogene. 23:1507-1513.
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.
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 of DNA binding: possible role for interactions between Skn-1a and CBP/p300. J. Biol. Chem. 276:33036-33044.
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., 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.
Society for Developmental Biology
The Endocrine Society
Society for Investigative Dermatology
Cellular and Molecular Biosciences
UCI Cancer Center and Cancer Research Institute
Institute for Genomics and Bioinformatics
Sue & Bill Gross Stem Cell Research Center