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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?
We have performed microarray analysis to define the gene expression changes that occur with quiescence. In order to delineate the signaling network that produces these gene expression changes, we developed a new computational algorithm COALESCE that co-clusters genes based on both gene testing specific motifs and transcription factors as potential “master regulators” of quiescence.
We also hypothesized that microRNAs might regulate quiescence. In collaboration with Rosetta Inpharmatics, we monitored the expression levels of ~200 microRNAs over a time course as fibroblasts become quiescent and then re-entered the cell a group of microRNAs downregulated with quiescence, some by as much as 8-fold. Overexpression of specific microRNAs upregulated with quiescence affect the cell cycle as quiescent cells are induced to proliferate.
In addition, we are exploring the changes in histone modifications that occur with quiescence. We have identified changes in the histone code specific for 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 distinction in TCA cycle usage in proliferating versus quiescent cells, and are exploring 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.
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. We are developing methods to identify growing and quiescent fibroblasts in tissue samples, and using these markers to monitor the expression of genes important for quiescence.
The identification of different quiescent states may lead to a better understanding of context-specific control of cell growth during development and repair. Identification of specific genes that enforce quiescence may also lead to better strategies for controlling cell division, including the unchecked division of cancer.
Selected Publications:
Huttenhower C, Mutungu KT, Indik N, Yang W, Schroeder M, Forman JJ, Troyanskaya OG, Coller HA. (2009) Detailing regulatory networks through large scale data integration. Bioinformatics. [Epub ahead of print]
Huttenhower C, Haley EM, Hibbs MA, Dumeaux V, Barrett DR, Coller HA, Troyanskaya OG. (2009) Exploring the human genome with functional maps. Genome Res. 19: 1093-1106. PubMed
Legesse-Miller A, Elemento O, Pfau SJ, Forman JJ, Tavazoie S, Coller HA. (2009) let-7 overexpression leads to an increased fraction of cells in G2/M, direct down-regulation of Cdc34 and stabilization of Wee1 kinase in primary fibroblasts. J Biol Chem. 284: 6605-6609. PubMed
Coller HA, Kruglyak L. (2008) Genetics. It's the sequence, stupid! Science 322: 380-381. PubMed
Forman JJ, Legesse-Miller A, Coller HA. (2008) A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc Natl Acad Sci 105: 14879-14884. PubMed
Sang L, Coller HA, Roberts JM. (2008) Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science 321: 1095-1100. PubMed
Pollina EA, Legesse-Miller A, Haley EM, Goodpaster T, Randolph-Habecker J, Coller HA. (2008) Regulating the angiogenic balance in tissues. Cell Cycle 7: 2056-2070. PubMed
Goodpaster T, Legesse-Miller A, Hameed MR, Aisner SC, Randolph-Habecker J, Coller HA. (2007) An immunohistochemical method for identifying fibroblasts in formalin-fixed, paraffin-embedded tissue. J Histochem Cytochem. 56: 347-358. PubMed
Coller HA, Forman JJ, Legesse-Miller A. (2007) "Myc'ed messages": myc induces transcription of E2F1 while inhibiting its translation via a microRNA polycistron. PLoS Genet. 3: e146. PubMed
Coller HA. (2007) What's taking so long? S-phase entry from quiescence versus proliferation. Nat Rev Mol Cell Biol 8: 667-670. PubMed
Huttenhower C, Flamholz AI, Landis JN, Sahi S, Myers CL, Olszewski KL, Hibbs MA, Siemers NO, Troyanskaya OG, Coller HA. (2007) Nearest Neighbor Networks: clustering expression data based on gene neighborhoods. BMC Bioinformatics 8: 250. PubMed
Miller DL, Myers CL, Rickards B, Coller HA, Flint SJ. (2007) Adenovirus type 5 exerts genome-wide control over cellular programs governing proliferation, quiescence, and survival. Genome Biol 8: R58. PubMed
Munger J, Bajad SU, Coller HA, Shenk T, Rabinowitz JD. (2006) Dynamics of the cellular metabolome during HCMV infection, PLoS Pathogens 2: e132. PubMed
Coller HA, Sang L, Roberts J. (2006) A new description of cellular quiescence. PLoS Biol 4: e83. PubMed
Coller HA, Khrapko K, Herrero-Jimenez P, Vatland JA, Li-Sucholeiki XC, Thilly WG. (2005) Clustering of mutant mitochondrial DNA copies suggests stem cells are common in human bronchial epithelium. Mutat Res 578: 256-271. PubMed
Smith LL, Coller HA, Roberts J. (2003) Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat Cell Biol 5: 474-479. PubMed
Coller HA, Khrapko K,
Coller HA,* Grandori C,* Tamayo P, Colbert T, Lander ES, Eisenman RN, 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. PubMed
Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA,