miRNA function

Cell, Vol. 116, 281–297, January 23, 2004, Copyright 2004 by Cell Press

MicroRNAs: Genomics,
Biogenesis, Mechanism, and Function
David P. Bartel1,2,*
1
Whitehead Institute for Biomedical Research
9 Cambridge Center
Cambridge, Massachusetts 02142
2
Department of Biology
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139

MicroRNAs (miRNAs) are endogenous ‫ 22ف‬nt RNAs that can play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

In an investigation inspiring for both its perseverance and its scientific insight, Victor Ambros and colleagues,
Rosalind Lee and Rhonda Feinbaum, discovered that lin-4, a gene known to control the timing of C. elegans larval development, does not code for a protein but instead produces a pair of small RNAs (Lee et al., 1993).
One RNA is approximately 22 nt in length, and the other is approximately 61 nt; the longer one was predicted to fold into a stem loop proposed to be the precursor of the shorter one. The Ambros and Ruvkun labs then noticed that these lin-4 RNAs had antisense complementarity to multiple sites in the 3Ј UTR of the lin-14 gene
(Lee et al., 1993; Wightman et al., 1993). This complementarity fell in a region of the 3Ј UTR previously proposed to mediate the repression of lin-14 by the lin-4 gene product (Wightman et al., 1991). The Ruvkun lab went on to demonstrate the importance of these complementary sites for regulation of lin-14 by lin-4, showing also that this regulation substantially reduces the amount of LIN-14 protein without noticeable change in levels of lin-14 mRNA. Together, these discoveries supported a model in which the lin-4 RNAs pair to the lin-14 3Ј UTR to specify

References: Ambros, V. (1989). A hierarchy of regulatory genes controls a larvato-adult developmental switch in C. elegans. Cell 57, 49–57. M., et al. (2003a). A uniform system for microRNA annotation. RNA 9, 277–279. of genomic tandem repeats and transposable elements in Drosophila melanogaster germline. Curr. Biol. 11, 1017–1027. Aukerman, M.J., and Sakai, H. (2003). Regulation of flowering time and floral organ identity by a MicroRNA and its APETALA2-like target Bartel, B., and Bartel, D.P. (2003). MicroRNAs: At the root of plant development? Plant Physiol (2003). Human let-7 stem-loop precursors harbor features of RNase III cleavage products Bernstein, E., Caudy, A.A., Hammond, S.M., and Hannon, G.J. (2001). Development 130, 1493–1504. Sci. USA 99, 15524–15529. Catalanotto, C., Azzalin, G., Macino, G., and Cogoni, C. (2000). Gene silencing in worms and fungi Caudy, A.A., Myers, M., Hannon, G.J., and Hammond, S.M. (2002). Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev. 16, 2491–2496. Cerutti, L., Mian, N., and Bateman, A. (2000). Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain. Trends Biochem. Sci. 25, 481–482. Chalfie, M., Horvitz, H.R., and Sulston, J.E. (1981). Mutations that lead to reiterations in the cell lineages of C Chen, X. (2003). A MicroRNA as a Translational Repressor of APET- Review September 11, 2003. 10.1126/science.1088060. Hipfner, D.R., Weigmann, K., and Cohen, S.M. (2002). The bantam gene regulates Drosophila growth Chen, C.Z., Li, L., Lodish, H.F., and Bartel, D.P. (2004). MicroRNAs modulate hematopoietic lineage differentiation Houbaviy, H.B., Murray, M.F., and Sharp, P.A. (2003). Embryonic stem cell-specific microRNAs Cogoni, C., and Macino, G. (1999). Gene silencing in Neurospora crassa requires a protein homologous to RNA-dependent RNA polymerase (2000). An RNA-dependent RNA polymerase in Arabidopsis is required for posttranscriptional gene silencing mediated by a transgene but not by a virus. Cell 101, 543–553. Doench, J.G., Peterson, C.P., and Sharp, P.A. (2003). siRNAs can function as miRNAs (2003). Numerous microRNPs in neuronal cells containing novel microRNAs. RNA 9, 631–632. Dykxhoorn, D.M., Novina, C.D., and Sharp, P.A. (2003). Killing the messenger: short RNAs that silence gene expression Elbashir, S.M., Leneckel, W., and Tuschl, T. (2001a). RNA interference is mediated by 21- and 22- nucleotide RNAs. Genes Dev. 20, 6877–6888. 13, 1768–1774. (2000). AGO1, QDE-2, and RDE-1 are related proteins required for post-transcriptional gene silencing in plants, quelling in fungi, and RNA interference in animals. Proc. Natl. Acad. Sci. USA 97, 11650–