O'Connor Lab: Current Projects

Epigenetics, Dendritic Cell Development & Disease Diet (Vitamin D)

The awarding of the 2011 Nobel Prize in physiology or medicine to Ralph M. Steinman for the discovery of dendritic cells (DCs) emphasizes their central role in the immune system and disease (1). While multiple DC lineages exist, each with distinct genetic profiles, their epigenetic regulation has not been studied (2). Epigenetic modifications, which are stable through mitosis (3), control gene loci activity (4, 5) and shape transcription throughout the life of the cell and organism (Fig.1) (6-8). Working with Dr. Eveline Farias-Hesson, we utilize next-generation sequencing to analyze histones via ChIP-seq. ChIP-seq studies have emphasized the importance of examining multiple histone modifications in a contextualized histone code regulating individual cell type identity (9, 10).  Working with Dr. Sonia Leach, Director of Computational Biology at National Jewish Health, we have defined appropriate methodology to analyze ChIP-seq data.

Figure 1

 


Epigenetic Regulation of Lung Immunity & Asthma T-Cell Memory

The phrase, “You are what you eat”, is an appropriate summation of this collaboration between the O’Connor lab, Dr. Kelsey Gray and the Schwartz/Yang lab.  The fascinating realization that our environment has a direct impact on our biology at a molecular genetic level must reorient our notions of health and disease.  Working with Dr. Gray, we are examining how dietary Vitamin D influences the epigenetic regulation of immune cells and as a result, affects Asthma.

 

Transcription & Epigenetics (Ross M. Kedl, PhD collaboration)

Of all the public health initiatives currently utilized, the international vaccine programs are by far, the most successful in protecting humanity from disease. Specialized cells of the adaptive arm of the Immune System, called Memory Lymphocytes, mediate the specificity and long-term protection of vaccines. Working with Dr. Ross Kedl, we are examining the epigenetic mechanisms that regulate memory T cells.

 

Asthma, Lung Inflammation & T-Cell Skewing (Erwin W. Gelfand, MD collaboration)

Why do some people get sick and others not? The unique environment we experience each day plays a significant role in determining our health.  Working in collaboration with Dr. Erwin Gelfand, we are attempting to understand how the macro- and micro-environmental signals we experience each day, impacts the epigenetic regulation of Lung Inflammation and Asthma.

 

References

  1. Steinman, R.M., and J. Banchereau. 2007. Taking dendritic cells into medicine. Nature 449:419-426.

  2. Liu, K., G.D. Victora, T.A. Schwickert, P. Guermonprez, M.M. Meredith, K. Yao, F.F. Chu, G.J. Randolph, A.Y. Rudensky, and M. Nussenzweig. 2009. In vivo analysis of dendritic cell development and homeostasis. Science 324:392-397.

  3. Margueron, R., N. Justin, K. Ohno, M.L. Sharpe, J. Son, W.J. Drury, 3rd, P. Voigt, S.R. Martin, W.R. Taylor, V. De Marco, V. Pirrotta, D. Reinberg, and S.J. Gamblin. 2009. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461:762-767.

  4. Rugg-Gunn, P.J., B.J. Cox, A. Ralston, and J. Rossant. 2010. Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo. Proc Natl Acad Sci U S A 107:10783-10790.

  5. Vastenhouw, N.L., Y. Zhang, I.G. Woods, F. Imam, A. Regev, X.S. Liu, J. Rinn, and A.F. Schier. 2010. Chromatin signature of embryonic pluripotency is established during genome activation. Nature 464:922-926.

  6. Feser, J., D. Truong, C. Das, J.J. Carson, J. Kieft, T. Harkness, and J.K. Tyler. Elevated histone expression promotes life span extension. Mol Cell 39:724-735.

  7. Kioussis, D., and K. Georgopoulos. 2007. Epigenetic Flexibility Underlying Lineage Choices in the Adaptive Immune System. Science 317:620.

  8. Goldberg, A.D., C.D. Allis, and E. Bernstein. 2007. Epigenetics: a landscape takes shape. Cell 128:635-638.

  9. Rada-Iglesias, A., R. Bajpai, T. Swigut, S.A. Brugmann, R.A. Flynn, and J. Wysocka. 2011. A unique chromatin signature uncovers early developmental enhancers in humans. Nature

  10. Wei, G., L. Wei, J. Zhu, C. Zang, J. Hu-Li, Z. Yao, K. Cui, Y. Kanno, T.Y. Roh, W.T. Watford, D.E. Schones, W. Peng, H.W. Sun, W.E. Paul, J.J. O'Shea, and K. Zhao. 2009. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30:155-167.