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Ï㽶ÊÓƵi regulatory functions in development and the onset of cancer.

The relatively recent discovery that double-stranded Ï㽶ÊÓƵ (dsÏ㽶ÊÓƵ) and its functional derivatives (siÏ㽶ÊÓƵ) could mediate potent and specific gene silencing in a wide variety of species sparked a revolution in molecular biology. While first discovered in C. elegans, now a recognized group of related phenomena broadly conserved in eukaryotes is generally known as Ï㽶ÊÓƵ-mediated interference, or Ï㽶ÊÓƵi. Central actors to these phenomena are small ~18-25nt non-coding Ï㽶ÊÓƵs which are matured by the RNase type III Dicer, and assembled with the Argonaute proteins into a variety of effector silencing complexes.

Ï㽶ÊÓƵi was first recognized for its potential as a research tool and for the therapeutic promises it holds. It is now widely used in all fields of biomedical research. Soon after its discovery it became clear that the Ï㽶ÊÓƵi-related phenomena serve a profound physiological purpose.

In one such mechanism termed microÏ㽶ÊÓƵ-mediated silencing, small Ï㽶ÊÓƵs are derived from gene-encoded hairpins and negatively regulate gene expression by base-pairing and silencing messenger Ï㽶ÊÓƵ by post-transcriptional means. According to predictions, they exert a direct negative regulation pressure on more than 30% of the entire coding gene set. In agreement with such spectacular estimates, microÏ㽶ÊÓƵ targets have been implicated in the broadest range of cellular functions in developmental, and steady-state contexts. Consistently, some of the small Ï㽶ÊÓƵ expression events were recently shown to be functionally important for transformation and tumor growth.

More recently, yet novel Ï㽶ÊÓƵi-related phenomena have emerged. While Ï㽶ÊÓƵi was originally thought to be a sequence-directed innate immunity response, these new forms of Ï㽶ÊÓƵi (named here loosely endoÏ㽶ÊÓƵi) appear to serve other fundamental functions such as mediating heterochromatin formation or consolidation. Loss of machinery involved in endoÏ㽶ÊÓƵi results in a broad genetic instability, loss of chromosomes during mitosis, as well as localized and global gene mis-expression. Data from a variety of model systems support a model whereas small Ï㽶ÊÓƵs are derived from chromatin loci, and converge back on genomic regions to mediate changes in levels of chromatin folding by directing histone modifications. While these new functions for Ï㽶ÊÓƵi are only emerging, it is clear that they will have deep implications on our understanding of how the genome is organized and protected. They also offer a whole new set of possibilities to explain how cellular processes can be altered during the emergence of cancer.

My research program has two aims: 1- Understanding the molecular basis for the gene regulatory functions of endogenous Ï㽶ÊÓƵi, and 2- Defining small Ï㽶ÊÓƵ expression events, which are critical for development, and cancer ontogeny.