John L. Rinn
Department of Pathology
Broad Institute of MIT and Harvard
Research in our lab is motivated by a simple, but fascinating question : how does a cell know where it is in the body? In other words, how does the same genome that is present in every cell become programmed with distinct epigenetic landscapes that result in a wide range of cellular diversity?
For example the human skin regenerates nearly 1,000 times in a lifespan yet maintains intricate sites of cellular diversity, such as hair on the scalp, but not on the forehead or the palms of the hand. We recently discovered that adult human skin-fibroblasts exhibit specific gene expression programs, including the embryonic “HOX Code”, that are indicative of their location in the human body. Moreover, the “HOX Code” is required for patterning of the overlaying epithelia in human skin.
Remarkably, the skin “HOX Code” code is regulated, in part, by a large non-coding RNAs. One example was a large intergenic non-coding RNAs (lincRNA) termed HOTAIR that is encoded antisense to the human HOXC cluster, but surprisingly HOTAIR affects the global epigenetic state of the HOXD cluster located on a separate chromosome. Our goal is to understand the mechanisms by which lincRNAs like HOTAIR establish and maintain distinct epigenetic landscapes of both normal and cancer cells.
Current projects in the lab exploit multiple genomic technologies to systematically and comprehensively characterize the functional diversity of lincRNAs. We are using next generation sequencing to identify lincRNAs associated with different chromatin remodeling complexes and how these interactions may guide chromatin formation. In parallel, we are utilizing high-throughput loss of function studies to dissect the mechanistic roles of lincRNAs. As a third approach, we developed a lincRNA microarray to identify lincRNAs that are misregulated in a myriad of cancers. Together these efforts aim to unravel the functional diversity of the missing lincRNAs in genome regulation.
- A.M. Khalil, M. Guttman, M. Huarte, M. Garber, A. Raj, D. Rivera, K. Thomas, A. Presser, B. Bernstein, A. Oudenaarden, A. Regev, E.S. Lander* and J.L. Rinn*. Many Mammalian Large Intergenic Non coding RNAs Associate with Chromatin Modifying Complexes (2009). PNAS. Advanced Online Publication June 26, 2009
- M. Guttman, I. Amit, M. Garber, C. French, M.F. Lin, D. Feldser, M. Hurate, T.S. Mikkelsen, O. Zuk, N. Hacohen, B.E. Bernstein , M. Kellis, A. Regev, J.L. Rinn*, E.S. Lander*. Chromatin signature reveals more than a thousand highly conserved, large non-coding RNAs in mammals (2009) Nature. 2009 Mar 12;458(7235):223-7
- J.L. Rinn, J.K. Wang, N. Allen, S.A. Brugmann, A. Mikels, H. Liu, T. Ridky, H.S. Stadler, R. Nusse, J.A. Helms, H.Y. Chang. (2008). A dermal HOX transcriptional program regulates site-specific epidermal fate. Genes and Development. Feb 1; 22(3):303-307
- J.L. Rinn, M. Kertesz, J. Wang, S. Brunghman, H. Goodnough, B. Wong, M. Cleary, J.A. Helms, E. Segal, H.Y. Chang. (2007) Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Non-Coding RNAs. Cell. Jun 29;129(7):1311-23.
- J.L. Rinn, C. Bondre, H.B Gladstone, P.O. Brown and H.Y. Chang. (2006) Anatomic Demarcation by Positional Variation in Fibroblast Gene Expression Programs. PLoS Genetics. 2006 Jul;2(7):e119.
BBS webpage updated 12/02/2009