Massachusetts General Hospital

TGF-beta signaling regulates diverse process from normal development, wound healing and tissue homeostasis to tumor formation, fibrosis and metastasis. The pathway is mediated through activation of the transcription factors Smad2 and Smad3, which bind DNA in association with other transcription factors to regulate gene expression. Numerous different cell types in the body respond to TGF-beta signaling, but each cell type has a different response. Working in Richard Young’s Laboratory at the Whitehead Institute I discovered that key transcription factors that are required to determine cell identity also act to direct Smad transcription factors to their target genes, thus providing a mechanism for TGF-beta signaling to regulate genes most relevant to a specific cell type (Mullen et al., Cell, 2011). My laboratory builds on this foundation and uses a combined approach of genomics, genetics and biochemistry to study how TGF-beta signaling is targeted to new genes during development and how the transcriptional network of coding and non-coding genes targeted by TGF-beta signaling regulate development and disease.

Kaveh Daneshvar, PhD
Chan Zhou, PhD
Samuel York, Research Technician
Bo Tan, MD, Visiting Scientist

My laboratory focuses on understanding the transcriptional networks regulated by TGF-beta signaling in endodermal development and hepatic fibrosis.

Embryonic stem (ES) cells hold tremendous potential for regenerative medicine. Understanding how signaling pathways direct ES cell differentiation is key to harnessing this potential and to understanding how aberrations in these pathways lead to disease. We study how the TGF-beta signaling pathway regulates coding and non-coding genes to direct differentiation down the endodermal lineage, which gives rise to tissues of the gut and liver.

TGF-beta is a key signaling factor leading to hepatic fibrosis and end stage liver disease through activation of hepatic stellate cells. We are applying genome-wide approaches to identify the network of coding and non-coding genes regulated by TGF-beta signaling in the development of hepatic fibrosis.

Selected publications

1. Sigova, A.A., Mullen, A.C., Molinie, B., Gupta, S., Orlando, D.A., Guenther, M.G., Almada, A.E., Lin, C., Sharp, P.A., Giallourakis, C.C., Young, R.A. (2013). Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. Proc. Natl. Acad. Sci. USA 110, 2876-81.
2. Mullen, A.C., Orlando, D.A., Newman, J.J., Loven, J., Kumar, R.M., Bilodeau, S., Reddy, J., Guenther, M.G., DeKoter, R.P., and Young, R.A. (2011).  Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147, 565-576.
3. Pearce, E. L., Mullen, A. C., Martins, G. A., Krawczyk, C. M., Hutchins, A. S., Zediak, V. P., Banica, M., DiCioccio, C. B., Gross, D. A., Mao, C., Shen, H., Cereb, N., Yang, S. Y., Lindsten, T., Rossant, J., Hunter, C. A., and Reiner, S. L. (2003). Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302, 1041-1043.
4. Mullen, A. C., Hutchins, A. S., High, F. A., Lee, H. W., Sykes, K. J., Chodosh, L. A., and Reiner, S. L. (2002). Hlx is induced by and genetically interacts with T-bet to promote heritable T_H1 gene induction. Nature Immunology 3, 652-658.
5. Hutchins, A. S., Mullen, A. C., Lee, H. W., Sykes, K. J., High, F. A., Hendrich, B. D., Bird, A. P., and Reiner, S. L. (2002). Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell 10, 81-91.
6. Mullen, A. C., High, F. A., Hutchins, A. S., Lee, H. W., Villarino, A. V., Livingston, D. M., Kung, A. L., Cereb, N., Yao, T. P., Yang, S. Y., and Reiner, S. L. (2001). Role of T-bet in commitment of T_H1 cells before IL-12-dependent selection. Science 292, 1907-1910.
7. Mullen, A. C., Hutchins, A. S., Villarino, A. V., Lee, H. W., High, F. A., Cereb, N., Yang, S. Y., Hua, X., and Reiner, S. L. (2001). Cell cycle controlling the silencing and functioning of mammalian activators. Curr Biol 11, 1695-1699.