BBS Faculty Member - Alan Mullen

Alan Mullen

Department of Medicine

Massachusetts General Hospital
Thier Building, Room 306B
55 Fruit Street
Boston, MA 02114
Tel: 617-726-6342
Fax: 617-724-6518
Email: acmullen@mgh.harvard.edu
Visit my lab page here.



The vast majority of RNAs encoded by the human genome are never translated into protein, and our laboratory focuses on understanding how these noncoding RNAs regulate cell state in human development and disease. Long noncoding (lnc) RNAs have the same genomic structure as protein coding genes but are not translated into proteins. Instead, they carry out their primary biological functions as RNAs, including regulation of developmental and disease processes. Many lncRNAs are cell-type-specific and are also poorly conserved across species. Thus, the majority of lncRNAs expressed in human cells do not have identifiable homologues in murine cells. For this reason, we have chosen to study the role of lncRNAs in primary human cells.

Extracellular signals regulate cell state and differentiation. Our strategy is to apply sequencing approaches to identify lncRNAs that are directly induced by key signaling pathways that control differentiation. In particular, we are interested in how lncRNAs control the decision of human embryonic stem cells (hESCs) and human hepatic stellate cells to differentiate.

Human embryonic stem cell differentiation
hESCs can be propagated indefinitely and have the potential to differentiate into any cell in the adult human body, providing tremendous potential in regenerative medicine. TGF-beta signaling is a key pathway that maintains hESC state and also drives endodermal differentiation. We use gain and loss of function approaches to determine the role of lncRNAs in the differentiation of hESCs into endoderm with a focus on those that are directly regulated by TGF-beta signaling.

Human hepatic stellate cells.
Hepatic stellate cells make up 5-10% of the cells in the liver and are the cell type primarily responsible for hepatic fibrosis. Progressive liver fibrosis is driven in large part by TGF-beta signaling and is the common endpoint in every form of chronic liver disease. Fibrosis is significant because it is the underlying cause of end stage liver disease and liver failure. We are currently mapping the lncRNAs that are induced when nonfibrotic, quiescent hepatic stellate cells differentiate into fibrotic hepatic stellate cell myofibroblasts with a focus on identifying the lncRNAs that are directly regulated by TGFbeta signaling. We are employing gain and loss of function approaches to discover lncRNAs that are required for development of hepatic fibrosis with the goal of targeting these lncRNAs to treat fibrosis.



Last Update: 9/18/2017



Publications

For a complete listing of publications click here.

 


 

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 TH1 cells before IL-12-dependent selection. Science 292, 1907-1910.

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 TH1 gene induction. Nature Immunology 3, 652-658.

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. PMCID: PMC3212730.

Sigova, A.A,
Mullen, A.C.*, Moline, B, Gupta, S., Orlando, D.A., Guenther, M.G., Alamada, 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. Proceedings of the National Academy of Sciences USA 110, 2876-81. PMCID: PMC3581948.
*co-first author

Mullen, A.C. (2014). Hippo tips the TGF-beta scale in favor of pluripotency. Cell Stem Cell. 14, 6-8.



© 2016 President and Fellows
of Harvard College