Ramin Shiekhattar, Ph.D.
Professor of Human Genetics
Description of Research
Establishment and maintenance of cell identity is shaped by a set of core regulatory factors with positive and negative influences on gene expression leading to the assembly of specialized chromatin structures. Studies of non-coding RNAs, particular microRNAs and long non-coding RNAs (lncRNAs), have led to the proposal that non-coding RNAs may constitute such regulatory factors helping to balance the gene expression programs during development. While lncRNAs involved in such epigenetic programs such as X inactivation and imprinting confer silencing of gene expression, he has uncovered a class of lncRNAs that associate with the co-activator complex, Mediator, to positively regulate gene expression and chromatin architecture. This has led to a new paradigm in lncRNAs function as positive regulators of gene expression with tantalizing links to transcriptional enhancers.
- Isolation and characterization of BRCA1- and BRCA2-containing complexes in breast and ovarian cancers. - We have used biochemical and genomic approaches to delineate a mechanism of action for breast and ovarian cancer proteins with the goal of developing a rational therapeutic approach for two of the most deadly cancers affecting women in the United States.
- Characterization of the LSD1-CoREST complex in demethylation of nucleosomal substrates. - These studies led to the discovery that while LSD1 was able to demethylate recombinant histone H3 lysine 4 substrates, demethylation of nucleosomal substrates required the presence of CoREST. Moreover, we pinpointed the SANT domain of COREST as a critical domain in mediating such demethylation. This points to the SANT domain as an important target for therapeutic approach. Much like the new efforts to target the Bromo domain using iBET.
- Identification of small molecular inhibitor, Tranylcypromine as a specific inhibitor of LSD1. - These studies uncovered the monoamine oxidase inhibitor Tranylcypromine as a specific inhibitor of LSD1. A number of new studies have pointed to the therapeutic effects of Tranylcypromine and its derivatives in variety of cancers.
- Discovery of UTX, the first histone demethylase for H3 lysine 27. - This study identified UTX in a multiprotein complex with MLL3/4, the first enzyme complex opposing the action of the polycomb repressive complexes. UTX has been shown to be one of the highly mutated chromatin modifiers in cancer. Since mutations in UTX leads to increased levels of H3K27 methylation, cancers with UTX mutations could be the ideal targets for EZH2 inhibitors.
- Discovery of JARID1d, the first histone demethylase for H3 Lysine 4 trimethyl mark. - Identification of JARID1d in a complex with polycomb protein Ring6a revealed the intimate connection of a histone demethylase and polycomb repressive complexes. Other members of the JARID family have been linked with the development of a number of malignancies.
- Discovery of Activating noncoding RNAs (ncRNAs). - This is a paradigm shifting study delineating a class of long noncoding RNAs that activate transcription of their neighboring genes and thus act similar to classically defined enhancer elements. We find activating ncRNAs associate with the transcriptional co-activator, the Mediator complex, to promote DNA looping. These studies provide the foundation for analysis of activating ncRNAs.
- Discovery of Microprocessor. - Microprocessor is a complex composed of RNase III Drosha and the double-stranded RNA-binding protein DGCR8, required for the initial processing of primary microRNAs. This work has provided the framework for studies on the biogenesis and regulation of microRNA processing.
- Discovery of Integrator. - These studies culminated in the identification of a novel 12-subunit multiprotein complex that is intimately associated with the C-terminal domain of RNA polymerase II. We found that Integrator is required for the 3’-end processing of non-polyadenylated small nuclear RNA (snRNA) transcripts. Identification of Integrator has provided the framework for detailed analysis of snRNA transcription and RNA processing.
Selected Cancer-Related Publications
Leader of the Multidisciplinary Research Program: Cancer Epigenetics Program