The laboratory of Ramin Shiekhattar investigates the molecular mechanisms that underlie both cancer and gene regulation. In particular, the Shiekhattar laboratory explores how protein-coding genes are silenced and how disruption of gene silencing may lead to cancer. His work in the mechanics of gene regulation has led to his laboratory’s efforts in the field of epigenetics, the study of how certain molecules can change gene expression without changing the underlying DNA. In 2010, Shiekhattar published the discovery of long non-coding RNA, which his findings suggest may represent so-called gene enhancer elements—short regions of DNA that can increase gene transcription.

Shiekhattar earned his undergraduate degree in chemistry and doctorate degree in biochemistry at the University of Kansas. Following postdoctoral fellowships at Hahnemann University in Philadelphia and the University of Medicine and Dentistry of New Jersey, Shiekhattar joined The Wistar Institute as an assistant professor in 1997. In 2007, Shiekhattar began a sabbatical at Centre de Regulació Genòmica in Barcelona, Spain, as a Catalan Institution for Research and Advanced Studies (ICREA) professor. He returned to Wistar as a full professor in 2009.

The Shiekhattar laboratory’s cancer efforts focus on several important tumor suppressor genes related to familial cancer, such as BRCA1/BRCA2, which are associated with an increased risk for breast cancer. A number of human familial cancer syndromes are caused by the inheritance of a mutant allele of a tumor suppressor gene. These genes are involved in regulating cell growth, and they contribute to carcinogenesis when mutated or lost. The laboratory looks at how the protein products of these genes combine to form multi-protein complexes with other proteins. Through these efforts, the Shiekhattar laboratory has identified several new candidates for genes whose mutations may contribute to cancer

The Shiekhattar laboratory explores the epigenetic regulation of gene expression on a number of different fronts. Some proteins are responsible for the overall shape of DNA in a cell nucleus, in a structure called chromatin, while other enzymes are responsible for controlling how chromatin can be remodeled to provide access to individual genes. Recent evidence has implicated changes in chromatin structure as an important mechanism in gene regulation. Moreover, besides a classic role for proteins in mediating transcriptional and post-transcriptional effects, it has become clear that non-coding RNAs play an integral role in gene silencing by fine-tuning gene expression patterns during development and differentiation. Shiekhattar believes this “signaling by RNA” is an emerging field of research that will uncover novel pathways in genome organization and regulation.

1 - Lai F, Orom UA, Cesaroni M, Beringer M, Taatjes DJ,  Blobel GA, and Shiekhattar R.  Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature. 2013 (in press).

2 - Orom UA, Derrien T, Guigo R, Shiekhattar R., Long Noncoding RNAs as Enhancers of Gene Expression., Cold Spring Harbor Laboratory Symposia on Quantitative Biology. 2011 Apr 18., 21502407

3 - Orom UA, Shiekhattar R., Long non-coding RNAs and enhancers., Current Opinion in Genetics and Development. 2011 Apr;21(2):194-8., 21330130

4 - Orom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G,et al., Huang Q, Guigo R, Shiekhattar R., Long Noncoding RNAs with enhancer-like function in human cells., Cell. 2010 Oct 1;143(1):46-58. Comment in: Dev. Cell. 2010 Oct 19;19(4):P485-6.; Nat Methods. 2010 Dec;7(12):947., 20887892

5 - Fortschegger K, Shiekhattar R., Plant homeodomain fingers form a helping hand for transcription., Epigenetics. 2011 Jan 10;6(1)., 20818169

6 - Fortschegger K, de Graaf P, Outchkourov NS, van Schaik FM, Timmers HT, Shiekhattar R., PHF8 targets histone methylation and RNA polymerase II to activate transcription., Molecular and Cellular Biology. 2010 Jul;30(13):3286-98., 20421419

7 - Baillat D, Shiekhattar R., Functional dissection of the human TNRC6 (GW182-related) family of proteins., Molecular and Cellular Biology. 2009 Aug;29(15):4144-55., 19470757

8 - Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A., An operational definition of epigenetics., Genes and Development. 2009 Apr 1;23(7):781-3., 19339683

9 - Melo SA, Ropero S, Moutinho C, et al., Liu CG, Villanueva A, Capella G, Schwartz S Jr, Shiekhattar R, Esteller M., A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function., Nature Genetics. 2009 Mar;41(3):365-70. [Epub 2009 Feb 15] Erratum in: Nature Genetics. 2010 May;42(5):464., 19219043

10 - Savas JN, Makusky A, Ottosen S, Baillat D, Then F, Dranic D, Shiekhattar R, et al., Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies., Proceedings of the National Academy of the Sciences, USA. 2008 Aug 5;105(31):10820-5., 18669659

11 - Messick TE, Russell NS, Iwata AJ, Sarachan KL, Shiekhattar R, Shanks JR, Reyes-Turcu FE, Wilkinon KD, Marmorstein R., Structural basis for ubiquitin recognition by the otu1 ovarian tumor domain protein., Journal of Biological Chemistry. 2008 April 18; 283(16):11038-49., 18270205