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Multi-layered regulation of let-7 miRNA biogenesis determines cellular proliferation versus differentiation

Zoya Kai

Appointment Period: 2010-2011, Grant Years: [26]

Zoya KaiMicroRNAs (miRNAs) comprise a newly discovered class of gene regulatory molecules, and misregulation the expression and function of specific miRNAs contribute to oncogenesis. Human let-7 miRNAs have anti-proliferative functions and down-regulation of let-7 is associated with many cancers, including lung, breast and colon. In C. elegans, small changes in the timing of expression or the levels of the let-7 miRNA result in profound developmental abnormalities and lethality of the animal, indicating that tightly controlled mechanisms maintain proper levels of let-7. 

My thesis project aims to elucidate how expression of the let-7 miRNA is regulated during normal development. I found that transcription of the let-7 gene cycles during development, and I identified a novel cis element that regulates expression of let-7 in the intestine of C. elegans. Though let-7 has been implicated in human colon cancer, nothing is known about what regulates let-7 expression in this tissue and, thus, my work in C. elegans may start to shed some light on this regulation. Additionally, I developed a powerful reporter screen to identify transcription factors that regulate expression of let-7, and a manuscript detailing the cis and trans acting factors that control expression of let-7 miRNA during development is in preparation

My work has also revealed two important layers of post-transcriptional regulation that determine the timing and levels of let-7 miRNA during development across species. In collaboration with a post doc in the Pasquinelli lab, I identified the well-conserved LIN-28 protein as a repressor of the first step of let-7 processing. The mechanism by which LIN-28, an RNA-binding protein, negatively regulates expression of the let-7 miRNA is important for understanding pluripotency and developmental timing, as well as oncogenesis. Finally, working with another post-doc, I have uncovered a novel mechanism whereby the let-7 miRNA directly regulates its own biogenesis. Auto-regulation of let-7 expression is likely to be an important mechanism across species for controlling precise levels of this essential miRNA. In summary, my thesis research reveals new steps in the regulation of miRNA biogenesis and deepens our understanding of how the expression of let-7 can be misregulated during oncogenesis.

Kai Z, Pasquinelli AE. A genome wide view of hunchback-like-1 targets. Cell Cycle. (2010) 9:230-1. PMID: 20061795.

Kai ZS, Pasquinelli AE. MicroRNA assassins: factors that regulate the disappearance of miRNAs. Nat Struct Mol Biol. (2010) 17:5-10. PMID: 20051982.

Van Wynsberghe PM, Kai ZS, Massirer KB, Burton VH, Yeo GW, Pasquinelli AE. LIN-28 co-transcriptionally binds primary let-7 to regulate miRNA maturation in Caenorhabditis elegans. Nat Struct Mol Biol. (2011) 18:302-8. PMID: 21297634; PMCID: PMC3077891.

Zisoulis DG*, Kai ZS*, Chang R, Pasquinelli AE. Auto-regulation of miRNA biogenesis by let-7 and Argonaute. Nature, (2012) In revision. (* denotes co-first authors)

Hunter S, Finnegan E, Zisoulis DG, Kai ZS, Zisoulis, Melnik-Martinez KV, Pasquinelli AE, A network of let-7 targets regulates cellular differentiation in C. elegans. (2012) In preparation.