Molecular Biology Faculty

Hilary A. Coller

This email address is being protected from spambots. You need JavaScript enabled to view it.	Coller Research Lab
(609) 258-8466	Lewis Thomas Lab, 140
	Lab (609) 258-9243
Faculty Assistant	Leland Burnham
This email address is being protected from spambots. You need JavaScript enabled to view it.	(609) 258-1694

Research Focus

Genomic approaches to cell cycle and cancer

The Coller lab uses genomic approaches to gain insight into cell cycle control in normal tissues and cancer. Because uncontrolled cell division is so dangerous for an organism, the well-behaved cell must know not only when to divide, but—crucially—when not to. Shutting down cell division prevents tumors and maintains the proper form of tissues. Many cells, though, including fibroblasts, must also retain the ability to start dividing again when conditions are right—when the organism must grow, or a damaged tissue must be repaired. A cell in such a temporary, non-dividing state is said to be "quiescent." Signals that send a cell into quiescence include loss of contact with the underlying surface, too much contact with neighboring cells, and not receiving specific growth factors from the surroundings.

Despite its importance, little is known about the quiescent state. We have defined the genetic underpinnings of quiescence, showing that it is actively maintained by a host of genes. Different signals induce genetically different quiescence states, but all share a core set of genes that define a "quiescence program." These gene changes distinguish quiescence from irreversible non-dividing states, such as terminal differentiation. Research in the Coller laboratory includes the following projects:

How is the quiescence gene expression program regulated?

Many different genetic pathways change in expression between proliferation and quiescence, such as autophagy, extracellular matrix interactions, and protein secretion pathways, but few of the regulatory mechanisms in quiescent cells are known. Because previous studies have shown that miRNAs regulate many of these same pathways in several cell types, we hypothesized that microRNAs are important regulators for the cellular function of quiescent human fibroblasts. Using microRNA microarrays, we discovered that the majority of miRNAs monitored changed in expression level in proliferating versus quiescent fibroblasts. Overexpression studies revealed specific phenotypes for let-7b—which resulted in slower cell cycle re-entry from quiescence—and miR-29b—which resulted in repression of the target protein collagen IIIα1 (COL3A1) in cellular lysates and conditioned medium. We discovered that there is a network of microRNA changes that occur with quiescence and that the microRNAs within this network have a functional role in quiescence-associated changes in gene expression, cell cycle and extracellular matrix secretion.

We are now extending this work to understand trancript degradation rates for all transcripts within the cell in proliferating and quiescent cells. We are taking experimental and computational approches to define the most important contributors to transcript degradation rates, including investigating cross-talk between microRNAs and RNA binding proteins.

In addition, we are exploring the changes in histone modifications that occur with quiescence. We have identified specific histone modifications that are present at higher levels in quiescent cells and we are exploring the functional significance of these changes.

Characterization of the functional attributes of quiescent cells

We discovered that primary fibroblasts induced into proliferative quiescence by contact inhibition maintain a high metabolic rate. This finding contradicts the commonly held perception that decreased metabolism is a hallmark of quiescence. We have also discovered differences in usage of the pentose phosphate pathway and the TCA cycle in proliferating versus quiescent cells. We are developing biochemical assays to determine the mechanistic basis for these differences.

We have also discovered that autophagy is induced in quiescent fibroblasts. The induction of autophagy even in the presence of nutrients is paradoxical given the presumed role of autophagy as supplying nutrients under starvation conditions. We hypothesize that autophagy is important for quiescence because it increases protein and fatty acid turnover to ensure that damaged macromolecules do not accumulate under conditions in which they which cannot be diluted by transmission to progeny cells. In particular, we discovered that quiescent fibroblasts induce selective mitophagy that results in the degradation of mitochondria that are damaged or leaky.

Characterization of quiescence in vivo

Our goal is to translate our findings to understanding cell cycle control in the body, and the lack of control that results in cancer, fibrosis and other diseases. Toward this end, we are working with mouse models that allow us to test the specific hypotheses that we have developed in the laboratory in vivo. We are specifically testing whether autophagy and mitophagy change with quiescence in mouse models. We are also working with lymphocytes isolated from mice as an alternate quiescence model system.

Selected Publications

Coller, H.A. (2013) Introducing the Systems Biology of Cell State Regulation Section of Physiological Genomics. Physiological Genomics, April 30.

Evertts AG, Zee BM, Dimaggio PA, Gonzales-Cope M, Coller HA, Garcia BA. (2013) Quantitative dynamics of the link between cellular metabolism and histone acetylation. J Biol Chem. Mar 12. [Epub ahead of print]

Suh EJ, Remillard MY, Legesse-Miller A, [...] Coller HA. (2012) A microRNA network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts. Genome Biol. 13: R121. Pubmed

Legesse-Miller A, Raitman I, Haley EM, Liao A, Sun LL, Wang DJ, Krishnan N, Lemons JM, Suh EJ, Johnson EL, Lund BA, Coller HA. (2012) Quiescent fibroblasts are protected from proteasome inhibition-mediated toxicity. Mol Biol Cell. 23: 3566-3581. Pubmed

Wang DJ, Legesse-Miller A, Johnson EL, Coller HA. (2012) Regulation of the let-7a-3 promoter by NF-κB. PLoS One. 7: e31240 PubMed

Valcourt JR, Lemons JM, Haley EM, Kojima M, Demuren OO, Coller HA. (2012) Staying alive: Metabolic adaptations to quiescence. Cell Cycle. 11: 1680-1696. PubMed

Ventura-Clapier R, Coller HA. (2012) A step toward systems metabolomics. Physiol Genomics. 44: 383-385. PubMed

Coller, Hilary A. (2011) The essence of quiescence. Science. 334: 1074-1075 Reprint | Full Text

Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemmons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E. (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25: 460-470. PubMed

Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, Rabinowitz JD, Coller HA, Thompson CB. (2010) The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 24: 2784-2799. PubMed

Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, Pollina EA, Rabitz HA, Rabinowitz JD, Coller HA. (2010) Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol. 8: e1000514. (Selected for Nature Research Highlights and Faculty of 1000).

Ward, P.S., Patel, J., Wise, D.R. [...] Coller, H.A. [...] and Thompson, C.B. (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that convert a-ketoglutarate to 2-hydroxyglutarate, Cancer Cell, 17(3): 225-234.

Forman JJ, Coller HA. (2010) The code within the code: MicroRNAs target coding regions. Cell Cycle. 9(8): 1533-1541.Sang, L., Roberts, J.M. and Coller, H.A. (2010) Hijacking Hes1: Tumors co-opt the anti-differentiation strategies of quiescent cells, Trends in Molecular Medicine, 16: 17-26.

Huttenhower, C.*, Mutungu, K.T.*, Indik, N., Yang, W., Schroeder, M. Forman, J.J., Troyanskaya, O.G.* and Coller, H.A.* (2009) Detailing regulatory networks through large scale data integration, Bioinformatics, 25(24): 3267-3274.

Sang, L. and Coller, H.A. (2009) Fear of commitment: Hes1 protects quiescent fibroblasts from irreversible cellular fates, Cell Cycle, 8(14): 2161-2167.

Huttenhower, C.*, Haley, E.M.*, Hibbs, M.A., Dumeaux, V., Coller, H.A.* and Troyanskaya, O.G.* (2009) A functional map of the human genome, Genome Research, 9(6):1093-106.

Legesse-Miller, A., Elemento, O., Pfau, S., Forman, J.J., Tavazoie, S. and Coller, H.A. (2009) let-7 overexpression leads to G2/M arrest, direct down-regulation of Cdc34 and stabilization of Wee1 kinase in primary fibroblasts, Journal of Biological Chemistry, 284(11): 6605-6609.

Coller, H.A. and Kruglyak, L. (2008) It’s the sequence, stupid! Science, 322(5900): 380-381.

Forman, J.J., Legesse-Miller, A. and Coller, H.A. (2008) A search for highly conserved sequences in coding regions finds that let-7 targets Dicer within its coding sequence, Proc. Natl. Acad. Sci. USA, 105(39): 14879-14884.

Sang, L., Coller, H.A., and Roberts, J.M. (2008) HES1 regulates the reversibility of cellular quiescence, Science, 321(5892): 1095-1100.

Pollina, E., Legesse-Miller, A., Haley, E., Goodpaster, T., Randolph-Habecker, J. and Coller, H.A. (2008) Regulating the angiogenic balance in tissues: A potential role for the proliferative state of fibroblasts, Cell Cycle, 7(13): 2056-2070.

Goodpaster, T., Legesse-Miller, A., Hameed, M., Aisner, S., Randolph-Habecker, J. and Coller, H.A. (2008) An immunohistochemical method for identifying fibroblasts, Journal of Histochemistry and Cytochemistry, 56(4): 347-358.

Coller, H.A., Forman, J.J. and Legesse-Miller, A. (2007) “Myc’ed” messages: Myc induces transcription of E2Fs while inhibiting their translation via a microRNA polycistron that may serve as a signal integrator, PLoS Genetics, 3(8): e146. PMC1959363.

Huttenhower, C., Flamholz, A., Landis, J., Sahi, S., Myers, C., Hibbs, M., Siemers, N., Troyanskaya, O. and Coller, H.A. (2007) Nearest Neighbor Networks: Clustering expression data based on gene neighborhoods, BMC Bioinformatics, 8(1): 250. PMC1941745.

Coller, H.A. (2007) What’s taking so long? S-phase entry from quiescence versus proliferation, Nature Reviews Molecular Cell Biology, 8(8): 667-670.

Miller, D.L., Myers, C., Rickards, B., Coller, H. and Flint, S.J. (2007) Adenovirus type 5 exerts genome-wide control over cellular programs governing cell proliferation, quiescence and survival, Genome Biology, 8(4): R58. PMC1896011.

Munger, J., Bajad, S.U., Coller, H.A., Shenk, T. and Rabinowitz, J.D. (2006) Dynamics of the cellular metabolome during HCMV infection, PLoS Pathogens, 2(12): e132. PMC1698944.

Coller, H.A.*, Sang, L.* and Roberts, J.M. (2006) A new description of cellular quiescence. PLoS Biol. 4: e83. PMC1393757.

Zheng, W., Khrapko, K., Coller, H.A., Thilly, W.G. and Copeland, W.C. (2006) Origins of human mitochondrial point mutations as DNA polymerase gamma-mediated errors. Mutat Res. 599: 11-20.

Coller, H.A., Khrapko, K., Herrero-Jimenez, P., Vatland, J.A., Li-Sucholeiki, X.C. and Thilly W.G. (2005) Clustering of mutant mitochondrial DNA copies suggests stem cells are common in human bronchial epithelium. Mutat Res, 578: 256-271.

Smith, L.L.,* Coller, H.A.* and Roberts, J. (2003) Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat Cell Biol. 5: 474-479.

Staunton, J.E., Slonim, D.K., Coller, H.A., Tamayo, P., Angelo, M.J., Scherf, U., Weinstein, J.N., Park, J., Mesirov, J.P., Lander, E.S. and Golub, T.R. (2001) Chemomsensitivity prediction by transcriptional profiling. Proc. Natl. Acad. Sci. USA, 98:10787-10792. PMC58553.

Coller H.A., Khrapko, K., Bodyak, N.D., Nekhaeva, E., Herrero-Jimenez, P., and Thilly, W.G. (2001) High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nature Genetics 28:147-50.

Khrapko, K., Coller, H.A., Li-Sucholeiki, X.C., Andre, P.C., Thilly, W.G. (2001) High resolution analysis of point mutations by constant denaturant capillary electrophoresis (CDCE). Methods Mol. Biol. 163: 57-72.

Coller, H.A.,* Grandori, C.,* Tamayo, P., Colbert, T., Lander, E.S., Eisenman, R.N., and Golub, T. (2000) Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc. Natl. Acad. Sci. USA 97: 3260-3265. PMC16226.

Golub, T.R., Slonim, D.K., Tamayo, P., Huard, C., Gaasenbeek, M., Mesirov, J.P., Coller, H., Loh, M.L., Downing, J.R., Caligiuri, M.A., Bloomfield, C.D. and Lander, E.S. (1999) Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286: 531-537.

Coller, H.A., Khrapko, K., Torres, A., Frampton, M., Utell, M. and Thilly, W. (1998) Mutational spectra of a 100 base pair mitochondrial DNA target sequence in bronchial epithelial cells: a comparison of smoking and nonsmoking twins. Cancer Research 58: 1268-1277.

Khrapko, K., Coller, H.A., Hanekamp, J. and Thilly, W. (1998) Identification of sequence variants in mixtures by capillary electrophoresis hybridization. Nucleic Acids Research 26: 5738-5740.