"Misexpression of the Caenorhabditis elegans miRNA let-7 Is Sufficient to Drive Developmental Programs".

G.D. Hayes and  G. Ruvkun

Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114

The Caenorhabditis elegans microRNAs (miRNAs) lin-4 and let-7 promote transitions between stage-specific events in development by down-regulating the translation of their target genes. Expression of let-7 is required at the fourth larval stage for the proper transition from larval to differentiated, adult fates in the hypodermis; however, it was not known whether expression of let-7 is sufficient to specify these adult fates. To test this, we created fusion genes between lin-4 and let-7 that direct the expression of let-7 two stages early, at the L2 stage. We find that animals bearing the fusion genes show precocious adult development at the L4 stage, indicating that temporal misexpression of let-7 is sufficient to direct the larval-to-adult transition. Additionally, an RNA interference (RNAi)-based screen for enhancers of the precocious phenotype identified the period ortholog lin-42, among other genes, which are candidate modulators of the effects of let-7 expression. let-7 is conserved throughout bilaterian phylogeny, and orthologs of its targets have roles in vertebrate development, suggesting the importance of understanding how let-7 promotes terminal differentiation in C. elegans and other organisms.

Additional references:

1. Takamizawa, J., Konishi, H., Yanagisawa, K., Tomida, S., Osada, H., Endoh, H., Harano, T., Yatabe, Y., Nagino, M., Nimura, Y., Mitsudomi T,  and Takahashi T,  (2004). Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64, 3753–3756, (2004).

2. Hovsepian JA, and Frenster JH, "Reprogramming as an Approach to Neoplasms", (2004).

3. Johnson, S.M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., Labourier, E., Reinert, K.L., Brown, D., and Slack, F.J. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647, (2005).

4. Eder M, and Scherr M, "MicroRNA and Lung Cancer", (2005).

5. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu C-G, Croce CM, and Harris CC, (2006).
"Unique microRNA molecular profiles in lung cancer diagnosis and prognosis".

6. Mayr C, Hemann MT, and Bartel DP, (2007).
"Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation".

7. DeCarvalho S, "Effect of RNA from Normal Human Marrow on Leukaemic Marrow In-Vivo", (1963).

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