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Small Noncoding RNAs That Repress Transcription

Earlier in this chapter we mentioned that some genes are transcribed but not elongated. In many such instances, such genes are often located in the heterochromatin—that region of the genome where the DNA is tightly coiled and transcription is inhibited by the packed nucleosomes. Volpe and colleagues (2002; 2011) discovered that if they deleted the genes in yeast encoding the appropriate RNases or RISC proteins, the heterochromatin around the centromeres became unpacked, the histones in this region lost their inhibitory methylation, and the centromeric heterochromatin started making RNA. Similar phenomena were seen when these proteins were mutated in Drosophila (Pal-Bhadra et al. 2004).

It appears that microRNAs are able to bind to the nuclear RNA as it is being transcribed, and form a complex with the methylating and deacetylating enzymes, thus repressing the gene. If synthetic microRNA made complementary to specific promoters is added to cultured human cells, that microRNA is able to induce that promoter’s DNA to become methylated. Lysine 9 on histone H3 also becomes methylated around the promoter, and transcription from that gene stops (Kawasaki and Taira 2004; Morris et al. 2004).

This appears to be the mechanism by which NRSF/REST (see pp. 46 and 355 of the textbook) functions. NRSF prevents gene expression in non-neural cells by repressing microRNAs that would otherwise recruit histone acetyltransferases to activate genes that promote neuron production. In the presence of NRSF, these miRNAs are not present, so histone deacetylases and methyltransferases are recruited to the chromatin instead. The resulting methylation produces conglomerations of nucleosomes linked together by heterochromatin protein-1 (HP1), thereby stabilizing the conglomerate and preventing transcription of the neuron-promoting genes “hidden” within it (Ooi and Wood 2007; Yoo et al. 2009.) A single silencer protein bound to the DNA can prevent the gene’s expression.

Thus, microRNA directed against the 3¢ end of mRNA may be able to shut down gene expression on the translational level, while microRNA directed at the promoters of genes may be able to block gene expression at the transcriptional level. The therapeutic value of these RNAs in cancer therapy is just beginning to be explored (see pp. 659–660 of the textbook.)

Literature Cited

Pal-Bhadra, M., Leibovitch, B. A., Gandhi, S. G., Chikka, M. R., Bhadra, U., Birchler, J. A., and Elgin, S. C. 2004. Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science 303: 669–672.

Kawasaki, H., and Taira, K. 2004. MicroRNA-196 inhibits HOXB8 expression in myeloid differentiation of HL60 cells. Nucleic Acids Symp Ser 2004: 211–212.

Morris K. V., Chan S. W., Jacobsen S. E., and Looney D. J. 2004. Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305: 1289–1292.

Ooi L., and Wood I. C. 2007. Chromatin crosstalk in development and disease: lessons from REST. Nature Rev Genet. 8: 544–554.

Volpe, T. A., Kidner, C., Hall, I. M., Teng, G., Grewal, S. I., and Martienssen, R. A. 2002. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297: 1833–1837.

Volpe, T., and Martienssen, R. A. 2011. RNA interference and heterochromatin assembly. Cold Spring Harb Perspect Biol. 3(9):a003731.

Yoo, A. S., Staahl, B. T., Chen, L., and Crabtree, G. R. 2009. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460: 642–646.

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