The Agami Group

Identifying and characterizing cancerous genes; Focus on RNA

Our main research objective is to understand the cancerous process in humans and identify essential cancerous genes.
We believe that the knowledge obtained on these genes will allow us to design in the future novel therapeutic approaches.

Research line 1: Functional screens using RNAi. Most human tumors harbor multiple genetic alterations that activate oncogenes, inhibit tumor suppressors and induce genomic instability. As each tumor contains many genetic alterations, the study of the contribution of each alteration to the cancerous phenotype was obscured. In the past, we developed and successfully used an RNA interference (RNAi) approach to inactivate genes in mammalian cells. We used this RNAi system to characterize tumor suppressors and novel components of DNA damage signaling components.

Research line 2: Functional screens for cancerous miRNAs. In the past years we initiated studies to identify cancerous microRNAs (miRNAs), a newly emerging gene family encoding for endogenous small RNAs. We developed and are still using novel and unique genetic approaches to screen for cancer-causing and cancer-preventing miRNAs.

Research line 3: Interplay between miRNAs and RBPs. Interestingly, we noticed that the regions surrounding some functional miRNA targets (identified by our genetic screens) are highly conserved throughout evolution. We hypothesized that these regions recruit RNA binding proteins (RBPs) that regulate miRNA function. We performed genetic screens and identified and characterized RBPs that can inhibit or potentiate the accessibility of miRNAs to their target mRNAs. We suggest that the genetic interaction between miRNAs and RBPs influence developmental processes, cellular proliferation, and cancer.

Research line 4: Regulation of alternative polyadenylation. Alternative cleavage and polyadenylation of mRNAs (APA) is emerging as an important layer of gene regulation as the majority of mammalian genes were already demonstrated to contain multiple polyadenylation (poly(A) sites in their 3' UnTranslated Regions (3’UTRs). Significant change in APA is observed when cells were stimulated to proliferate, differentiate, and during cancer progression. We uncovered the role of in APA and link it with a human genetic disorder.

Research line 5: eRNAs It is well known that the p53 tumor suppressor gene regulates transcription and cell cycle progression by binding within or nearby target genes controlling cell proliferation and survival. We found that p53 binds genomic regions located distantly from any known p53 target gene. Interestingly, many of these regions possess conserved p53-binding sites and all known hallmarks of enhancer regions. We demonstrate that these p53-bound regions are indeed enhancers. Moreover, these p53-binding sites produce enhancer RNAs (eRNAs) that are required for enhancer activity. The production of eRNAs is interesting, as they can be used to control enhancer activity and phenotype.