BBS Faculty Member - John Rinn

John Rinn

Department of Stem Cell and Regenerative Biololgy

Broad Institute of MIT and Harvard
7 Cambridge Center, 6047
Cambridge, MA 02142
Tel: 650-575-2591
Fax: 617-324-2722

Department of Stem Cell and Regenerative Biology
7 Divinity Ave., Room 205
Cambridge, MA 02138
Tel: 617-496-3561

Email: john_rinn@harvard.edu
Visit my lab page here.



A fundamental and unsolved problems in biology is: how does the same genome present in every cell encode a multitude of different cellular states? It is well established that epigenetic regulation plays a key role in this process, yet the array of these epigenetic landscapes are established by ubiquitously expressed chromatin remodeling complexes. It has long been suspected that non-coding RNA molecules to bring these complexes to their sites of action. Indeed, we and others have recently discovered several examples of large non-coding RNA molecules that ‘guide’ chromatin formation. Interestingly, these known examples (e.g. XIST, HOTAIR, and AIR) confer distinctive epigenetic states, yet share a common mechanism: they physically associate with chromatin remodeling complexes and ‘guide’ them to specific genomic loci. Here we show that large ncRNAs may be a general mechanism for the establishment and maintenance of epigenetic states in development and disease.

We recently discovered a new class of highly conserved large intergenic non-coding RNAs (lincRNAs) and a computational method to predict their functions. This “guilt by association method” pointed to a clear association of lincRNAs with chromatin remodeling complexes, particularly in the context of cancer and pluripotent cell states. Here, we present a systematic and comprehensive approach that demonstrates a majority of lincRNAs associate with various chromatin-remodeling complexes and regulate specific genomic sites in cancer and the derivation of induced pluripotent stem cells. As one example, we show that p53 directly and temporally induces several lincRNAs in response to DNA damage. Including lincRNA-p21 that is required for proper localization of chromatin factors to mediate p53 dependent cellular apoptosis. Together, these results point to key regulatory roles for lincRNAs across diverse biological pathways, through interfacing with and imparting specificity to chromatin modifying remodeling complexes.

We are actively exploring the roles of lincRNAs in the following areas:

1)
‘onco-RNAs’ and ‘tumor-suppressor-RNAs’ : By analyzing numerous emerging cancer atlases we are identifying candidate RNA genes that are misregulated in cancer and or genetic alteration of RNA genes in caner. Using several cell based assays we are identifying the mechanistic and tumorgenic potential of RNA genes.

2)
The role of large RNA genes in cell differentiation: We recently identified numerous lincRNAs that are required or play critical roles during adipogenesis and induced pluripotency amongst others. We are employing large scale Gain and Loss of function experiments to unravel how these RNA based perturbations affect cell circuitry.

3)
Structure and Function of Large RNA genes: We are exploring numerous non-canonical Ribonucleic interactions between lincRNAs and proteins that do not contain classic RNA binding domains. Using several approaches we are identifying the diversity of RNA genes bound to epigenetic machinery and how these interactions occur on a structural level.

4)
Synthetic RNA Biology: Using RNA as ‘tinker toys’ to build synthetic RNA-Protein interactions to modulate cell fate decisions. We are also exploring using RNA as small molecule screening approaches to identify synthetic RNAs that may guide cellular differentiation.

5)
Large RNA genes in Parasites: We recently identified a novel family of telomeric encoded large RNA genes in P. Falciparum Malaria. We are further investigating their potential in regulating virulence genes and or epigenetic regulation of telomeres.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Broadbent K, Park D, Wolf AR, Van Tyne D, Sims JS, Ribacke U, Volkman S, Duraisingh M, Wirth D, Sabeti PC*, Rinn JL*. A global transcriptional analysis of Plasmodium falciparum malaria reveals a novel family of telomere-associated lncRNAs. Genome Biol. 2011 Jun 20;12(6):R56. [Epub ahead of print]

S. Loewer, M. Guttman, Y.H. Loh, M. Garber, K. Thomas, I.H. Park 1, M. Curran, S. Agarwal, P. Manos, S. Datta, E.S. Lander, T. Schlaeger, G.Q. Daley* and
J.L. Rinn*. Large intergenic non-coding RNAs as novel regulators of induced pluripotent cell survival (2010). Nature Genetics. Dec;42 (12):1113-7. Epub 2010 Nov 7.

M. Huarte, M. Guttman, D. Feldser, M. Garber, A.M. Khalil, O. Zuk, I Amit, A. Regev, E.S. Lander, T. Jacks and
J.L. Rinn. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 transcriptional response (2010). Cell. Aug 6;142(3):409-19.

A.M. Khalil, M. Guttman, M. Huarte, M. Garber, A. Raj, D. Rivera, K. Thomas, A. Presser, B. Bernsteina,d, 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. Jul 14;106(28):11667-72. Epub 2009 Jul 1.

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. Mar 12;458(7235):223-7



© 2013 by the President and Fellows of Harvard College