Christopher M. Hammell
Ph.D., Dartmouth Medical School,2002
Post-transcriptional gene regulation; control of animal developmental timing; RNA biology
microRNAs (miRNAs) are ~22 nt RNAs that negatively regulate mRNA expression by binding to complementary sequences found in the 3'UTRs of their targets. The abundance of individual miRNAs can be regulated at the transcriptional level or by controlling their maturation from double stranded precursors (~70nt) to the mature ~22nt form. However, in contrast to transcriptional or processing control of miRNAs, little is known about the mechanisms whereby the efficacy (or biochemical activity) of miRNAs and the miRNA Induced Silencing Complex (miRISC) can be regulated in vivo.
Through forward genetic approaches in C. elegans, we have identified a variety of gene products that modulate the efficacy of and/or regulate the activity of the core miRNA machinery. These efforts have identified a novel, highly conserved family of proteins, the TRIM-NHLs, which physically associate with miRISC and function with particular miRNAs to regulate animal development. In addition to the TRIM-NHL proteins, these classical genetic approaches have also identified additional regulatory components that tailor miRNA function (via responding to other developmental cues or physiological signals) to specific genetic pathways and/or cell types. As most of the components identified in these screens are highly conserved, we are also utilizing additional model systems (including Drosophila, mouse and human) to understand how these proteins work at the molecular level.
iHammell, C.M., Karp, X. and Ambros, V. 2009. A feedback circuit involving let-7-Family miRNAs and DAF-12 integrates environmental signals and developmental timing in C. elegans. Proc. Natl. Acad. Sci. 106:1866–1873.
Hammell, C.M., Lubin, I., Boag, P.R., Blackwell, K.T., Ambros, V. 2009. nhl-2 modulates miRNA activity in Caenorhabditis elegans. Cell. 136:926–938.
Hammell, C.M. 2008. The microRNA-argonaute complex: a platform for mRNA modulation. RNA Biol. 5:123–127.