Richard A. Young

Signal transduction pathways

The Young laboratory is interested in the transcriptional control of cell identity and differentiation in mice and humans. We use experimental and computational technologies to determine how signaling pathways, transcription factors, chromatin regulators and small RNAs control gene expression programs in healthy and diseased cells.  Our interests range from the basic molecular mechanisms of gene control to development of drugs for cancer and other diseases caused by gene misregulation.

The Young laboratory has developed powerful genomics methods to investigate how transcriptional regulators control gene expression programs in healthy and diseased cells.  These methods have been used to discover how gene expression programs are controlled in embryonic stem cells, normal differentiated cells and in cancer cells. Among the key concepts that emerged from these studies is that transcription factors that control cell state typically regulate their own gene expression, that chromatin modifications span active genes in a spatially specific manner, and that signaling pathways have terminal kinases that generally occupy the set of genes they regulate.

The themes that best capture the current interests of the Young lab include transcriptional regulation, epigenetics, chromosome structure, stem cell biology, developmental biology, regenerative medicine, cancer and drug discovery. For example, we are mapping the transcriptional regulatory circuitry of mammalian cells, which involves a core circuitry consisting of master transcription factors and cofactors. This knowledge is facilitating efforts in our lab to reprogram cells for regenerative medicine. The relationships between gene regulation and chromosome structure are beginning to emerge from technologies that reveal DNA looping. Cancer and other diseases are frequently caused by misregulation of transcriptional and epigenetic regulators and we are interested in developing novel therapeutics that target this misregulation. Thus, our studies form the foundation for improved understanding of cellular regulation in human health and disease and for development of new therapies for disease.

Rahl, P.B., Lin, C.Y., Seila, A.C., Flynn, R.A., McCuine, S., Burge, C.B., Sharp, P.A., and Young, R.A. c-Myc Regulates Transcriptional Pause Release. Cell 141: 432–445 (2010).

Mullen, A.C., Orlando,D.A., Newman, J.J., Lovén, J., Kumar, R.M., Bilodeau, S., Guenther, M.G., DeKoter, R., and Young, R.A. Master transcription factors determine the gene targets of the TGF-β pathway. Cell 147: 565-576 (2011).

Young, R.A. Control of the embryonic stem cell state. Cell 144: 940-54 (2011).

Lin, C.Y., Lovén, J., Rahl, P.B., Paranal, R.M., Burge, C.B., Bradner, J.B., Lee, T.I., and Young, R.A. Transcriptional Amplification in Tumor Cells with Elevated c-Myc. Cell 151: 56-67 (2012).

Lovén, J., Orlando, D.A., Sigova, A., Lin, C., Rahl, P.B., Burge, C.B., Levens, D.L., Lee, T.I. and Young, R.A. Revisiting Global Gene Expression Analysis. Cell 151: 476-482 (2012).

Whyte, W.A., Bilodeau, S., Orlando, D.A., Hoke, H.H., Frampton, G.M., Foster, C.T., Cowley, S.M. and Young, R.A. Enhancer Decommissioning by LSD1 During Embryonic Stem Cell Differentiation.  Nature 482: 221-5 (2012).

Hnisz, D., Abraham, B.J., Lau A, Saint-André, V., Sigova, A.A., Hoke, H.A., Lee, T.I., and Young, R.A. Super-enhancers in the control of cell identity and disease. Cell 155: 934-947 (2013).

Lee, T.I. and Young, R.A. Transcriptional regulation and its misregulation in disease. Cell 152: 1237-1251 (2013).

Lovén, J., Hoke, H.A., Lin, C.Y., Lau, A., Orlando, D.A., Vakoc, C.R., Bradner, J.E., Lee, T.I. and Young, R.A. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell: 153: 320-334 (2013).

Whyte, W.A., Orlando, D.A., Hnisz, D., Abraham, B.J., Lin, C.Y., Kagey, M.H., Rahl, P.B., Lee, T.I., and Young, R.A.  Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153: 307–319 (2013).

Anders, L., Guenther, M.G., Qi, J., Fan1, X.P., Marineau, J.J., Rahl, P.B., Lovén, J., Sigova, A.A., Smith, W.B., Lee, T.I., Bradner, J.E. and Young, R.A. Genome-wide localization of small molecules. Nat Biotechnol 32:92-96 (2014).

Kwiatkowski, N., Zhang, T., Rahl, P.B., Abraham, B., Reddy, J., Ficarro, S., Dastur, A., Amzallag, A., Ramaswamy, S., Tesar, B., Jenkins, C.R., Hannett, N., McMillin, D., Sanda, T., Sim, T., Kim, N.D., Look, T., Mitsiades, C., Weng, A.P., Brown, J.R., Benes, C.H., Marto, J., Young, R. and Gray, N.S. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511: 616-620 (2014).