Lisa Ann Cirillo, PhD
Department of Cell Biology, Neurobiology & Anatomy
PhD, University of Illinois at Chicago, 1996
Medical College of Wisconsin
8701 Watertown Plank Road
Milwaukee, WI 53226-0509
Phone: (414) 955-4694
FAX: (414) 955-6517
PhD, University of Illinois at Chicago, 1996
Postdoctoral, Brown University and Fox Chase Cancer Center
Program in Cell and Developmental Biology
Positions are currently available for Postdoctoral Fellows. Please contact Dr. Lisa Cirillo at firstname.lastname@example.org
or visit our Postdoctoral Positions web page.
Research Area: Molecular mechanisms underlying liver development and function, with a particular focus on the role played by chromatin structure in the transcriptional regulation of liver genes.
The long term goal of the Cirillo laboratory is to uncover fundamental mechanisms which underlie the complex patterns of gene expression required for appropriate liver development and function, with a specific emphasis on the influence of chromatin structure. A critical, unresolved issue in gene regulation is the means by which the chromatin that packages developmentally regulated genes is accessed and remodeled to orchestrate cell-type specific gene expression programs. This poses a significant dilemma in cells of both the developing embryo, in which much of the chromatin is still compacted, and the adult organism, where alterations in gene expression in response to signaling cascades directing essential physiological functions necessitate rapid alterations in the chromatin landscape. Failure to properly navigate either of these biological challenges can have grave biomedical consequences in the form of congenital malformations, disease, and neoplasia. While there is much focus in the field on chromatin remodeling and modifying enzymes, numerous studies indicate that these proteins need to be recruited to their sites of action at gene regulatory regions by initial “pioneer” DNA binding factors that are the first to engage compacted, transcriptionally silent genes in development. Current research in the Cirillo laboratory is focused on gaining a mechanistic understanding of how one such pioneer factor, the forkhead transcription factor FoxO1, uses its ability to remodel compacted chromatin and cooperate with closely juxtaposed liver-enriched transcription factors to initiate changes in chromatin structure necessary for developmental activation and hormonal modulation of target genes that dictate key metabolic processes in the human liver. Our lab has recently demonstrated that FoxO1 is able to remodel linker histone-compacted chromatin and to recruit additional liver-enriched regulatory factors and RNA polymerase II to its regulatory targets in hepatic chromatin (Hatta and Cirillo, 2007, J. Biol Chem). Intriguingly, both of these activities are significantly curtailed by posttranslational modifications linked to signaling pathways with crucial roles in maintenance of glucose, bile acid and cholesterol homeostasis in humans (Hatta et al., 2009, Biochem Biophys Res Commun). FoxO1 is a key transcriptional regulator integrating hepatic glucose, cholesterol, bile acid, and lipid metabolism in humans; we propose that the chromatin binding and remodeling capabilities attributed to FoxO1 are essential for the assembly of the nucleoprotein structures tasked with activating the corresponding genes and mediating their response to diverse signaling pathways. Subversion of these gene regulatory events is a likely contributor to metabolic derangements and hepatic disease, making it vital that we uncover the key mechanisms and players. To accomplish this, we employ a repertoire of tissue culture-based approaches, including a novel human induced pluripotent stem (hiPS) cell hepatocyte differentiation system, to uncover basic molecular mechanisms informing the function and regulation of FoxO1 under conditions that recapitulate hepatocyte specification, differentiation, and function in humans. We combine this with state of the art molecular techniques that enable the assembly and analysis of defined chromatin structures (nucleosome particles and linker histone-compacted nucleosome arrays) to test mechanisms implicated by our observations.
Sarah Kohler and Lisa A. Cirillo (2010) Stable chromatin binding prevents FoxA acetylation, preserving FoxA chromatin remodeling. J. Biol. Chem. 285: 464-72.
Mounce BC, Tsan FC, Droit L, Kohler S, Reitsma JM, Cirillo LA, Tarakanova VL. (2011) Gammaherpesvirus gene expression and DNA synthesis are facilitated by viral protein kinase and histone variant H2AX.
Wu CH, Chen S, Shortreed MR, Kreitinger GM, Yuan Y, Frey BL, Zhang Y, Mirza S, Cirillo LA, Olivier M, Smith LM. (2011) Sequence-specific capture of protein-DNA complexes for mass spectrometric protein identification.
Mounce BC, Tsan FC, Kohler S, Cirillo LA, Tarakanova VL. (2011) Dynamic association of gammaherpesvirus DNA with core histone during de novo lytic infection of primary cells. Virology. 421: 167-72.
Hatta, M., Liu, F., and Cirillo, L.A.: Acetylation attenuates nucleosome binding, not stable nucleosome remodeling, by FoxO1. Biochem. Biophys. Res. Comm. Feb 20, 379 (4): pp. 1005-1008, 2009.
strong>Cirillo, L.A. and M.C. Barton. Many forkheads in the road to regulation. EMBO Reports. 9: pp 721-24, 2008.
Horswill, M.A, Narayan, M., Warejcka, D.J., Cirillo, L.A., and S.S. Twining: Epigenetic silencing of maspin expression occurs early in the conversion of keratocytes to fibroblasts. Exp. Eye Res., 2008.
Mitsutoki Hatta and Lisa A Cirillo: Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J. Biol. Chem. 262(49): 35583-35593, 2007.
Lisa A Cirillo and Ken Zaret: Stable interactions of the wing domains of FOXA1 transcription factor with DNA. J. Mol. Biol. 366(3): 720-4, 2007.
Taganov, K.D., Cuesta, I, Daniel, R., Cirillo, L.A., Katz, R.A., Zaret, K.S., and A. M. Skalka. Integrase-specific enhancement and suppression of retroviral DNA integration by compacted chromatin structure in vitro. J Virol. 78(11): 5848-55, 2004.
Deng Z, Chen CJ, Chamberlin M, Lu F, Blobel GA, Speicher D, Cirillo LA, Zaret K.S., and P.M. Lieberman. The CBP bromodomain and nucleosome targeting are required for Zta - directed nucleosome acetylation and transcription activation. Mol Cell Biol. 23(8): 2633-44,2003.
Cirillo LA, F Lin, I Cuesta, D Friedman, M Jarnik and KS Zaret: Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Molecular Cell 9:279-289, 2002.
Stevens K, LA Cirillo and KS Zaret: Creating temperature-sensitive winged-helix transcription factors: amino acids that stabilize the DNA binding domain of HNF3. Journal of Biological Chemistry 275:30471-30477, 2000.
Cirillo LA and KS Zaret: An early developmental transcription factor complex that is more stable on nucleosome core particles than on free DNA. Molecular Cell 4:961-969, 1999.
Cirillo LA, CE McPherson, P Bossard, K Stevens, S Cherian, EY Shim, KL Clark, SK Burley, and KS Zaret: Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO Journal 17:244-254, 1998.