During mammalian development, transcription factors and microRNAs both provide input to direct gene expression and determine lineage decisions. Some of these same pathways are recapitulated during oncogenesis and metastasis. Transcription factors controlling epithelial-mesenchymal transition are important both during development and in cancer. MicroRNAs are critical for control of gene expression and thus cell fate decisions and are often involved in temporal switches in lineage decisions. These two classes of developmental regulators have been shown to influence one another, but their mutual regulatory functions are not completely understood. I will use tissue culture and mouse models to study the interplay between EMT factors and microRNAs in development and cancer, and syngeneic, xenograft, and induced pluripotent stem cell models of ovarian cancer to study disease onset and progression.
During postdoctoral studies at Harvard Medical School, Dr. Unternaehrer studied the mechanism of reprogramming mouse and human somatic cells to pluripotency. Surprisingly, factors involved in EMT are upregulated and play a positive role in the early stages of the induced pluripotent stem (iPS) cell generation process. The microRNA let-7 is downregulated at time points when these factors are increased, and Snail binds the promoter of several let-7 family members. Lab members will use embryonic stem cell differentiation to model gastrulation, and cell lines to model ovarian cancer, to illuminate new points of regulation in these models, and develop new strategies for inhibiting cancer cell growth.
Dr. Unternaehrer studied the initiation of immune responses during Ph.D. studies at Yale, where she described molecular details of the interactions between dendritic cells and naïve CD4 T cells. She is interested to use iPS cells as a source of dendritic cells for tumor vaccines in ovarian cancer.Selcted Publications
1. Unternaehrer JJ, Zhao R, Kim K, Cesana M, Powers J, Ratanasirintrawoot S, Onder T, Shibue T, Weinberg R, Daley GQ. The epithelial-mesenchymal transition factor Snail paradoxically enhances reprogramming.
2. Shyh-Chang N, Locasale JW, Lyssiotis CA, Zheng Y, Teo RY, Ratanasirintrawoot S, Zhang J, Onder T, Unternaehrer JJ, Zhu H, Asara JM, Daley GQ, Cantley LC. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science. 2012 Nov 1.
3. Xu C, Fan ZP, Müller P, Fogley R, DiBiase A, Trompouki E, Unternaehrer JJ, Torregroza I, Evans T, Daley GQ, Schier AF, Young RA, Zon LI. nanog Regulates Endoderm Formation through the mxtx2-Nodal Pathway. Dev Cell. 2012 Mar 13;22(3):625-38.
4. Onder TT, Kara N, Cherry A, Sinha AU, Zhu N, Bernt KM, Cahan P, Marcarci BO, Unternaehrer J, Gupta PB, Lander ES, Armstrong SA, Daley GQ. Chromatin-modifying enzymes as modulators of reprogramming. Nature. 2012 Mar 4;483(7391):598-602.
5. Kim K, Zhao R, Doi A, Ng K, Unternaehrer J, Cahan P, Hongguang H, Loh YH, Aryee MJ, Lensch MW, Li H, Collins JJ, Feinberg AP, Daley GQ. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotechnol. 2011 Nov 27;29(12):1117-1119.
6. Unternaehrer JJ, Daley GQ.Induced pluripotent stem cells for modelling human diseases. Philos Trans R Soc Lond B Biol Sci. 2011 Aug 12;366(1575):2274-85.
7. Bloom O, Unternaehrer JJ, Jiang A, Shin JS, Delamarre L, Allen P, Mellman I. Spinophilin participates in information transfer at immunological synapses. J Cell Biol. 2008 Apr 21;181(2):203-11.
8. Jiang A, Ono S, Unternaehrer J, Jiang S, Whitney A, Connolly J, Banchereau J, Mellman I. E-cadherin/b-catenin signaling defines a distinct pathway of dendritic cell maturation. Immunity. 2007 Oct;27(4):610-24.
9. Unternaehrer JJ, Chow AY, Pypaert M, Inaba K, Mellman I. The tetraspanin CD9 mediates lateral association of MHC class II molecules on the dendritic cell surface. Proc Natl Acad Sci U S A. 2007. 104(1):234-9.
10. Tesar BM, Walker WE, Unternaehrer J, Joshi NS, Chandele A, Haynes L, Kaech S, Goldstein DR. Murine myeloid dendritic cell-dependent toll-like receptor immunity is preserved with aging. Aging Cell. 2006. 5(6):473-86.
12. Yan J, Wolff MJ, Unternaehrer J, Mellman I, Mamula MJ. Targeting antigen to CD19 on B cells efficiently activates T cells. Int Immunol. 2005. 17(7):869
13. Chow AY*, Unternaehrer JJ*, Mellman I. MHC class II. In Measuring Immunity: Basic Biology and Clinical Assessment. Edited by Michael T Lotze and Angus W Thomson. San Diego and London, Elsevier Academic Press. 2005.
14. Meyer zum Bueschenfeld C, Unternaehrer JJ, Mellman I, Bottomly K. Regulated recruitment of MHC class II and costimulatory molecules to lipid rafts in dendritic cells. J Immunol. 2004. 173(10):6119
15. Balamuth F, Leitenberg D, Unternaehrer J, Mellman I, Bottomly K. Distinct patterns of membrane microdomain partitioning in Th1 and Th2 cells. Immunity 2001. 15(5):729-38.
16. Turley SJ, Inaba K, Garrett WS, Ebersold M, Unternaehrer J, Steinman RM, Mellman I. Transport of peptide-MHC class II complexes in developing dendritic cells. Science 2000. 288(5465):522-7.
17. Gatti E, Velleca MA, Biedermann BC, Ma W, Unternaehrer J, Ebersold MW, Medzhitov R, Pober JS, Mellman I. Large-scale culture and selective maturation of human Langerhans cells from granulocyte colony-stimulating factor-mobilized CD34+ progenitors. J Immunol. 2000. 164(7):3600-7.
Zhao R, Deibler RW, Lerou PH, Ballabeni A, Heffner GC, Cahan P, Unternaehrer J, Kirschner MW, Daley GQ. A non-transcriptional role for Oct4 in the regulation of mitotic entry. PNAS 2014.
* equal contribution