Introduction to special issue

Freedom of Expression

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Science  28 Mar 2008:
Vol. 319, Issue 5871, pp. 1781
DOI: 10.1126/science.319.5871.1781

As in civil society, where there must necessarily be checks and balances on freedom of expression, cells have evolved a range of mechanisms to regulate the expression of their constituent genes. By far the best-understood medium for gene regulation is the protein transcription factor. The broad set of rules by which these regulators operate is outlined by Hobert (p. 1785). However, new and unexpected gene regulatory systems have been discovered in the past decade, perhaps the most important of which involve microRNAs (miRNAs). Hobert compares the action of these small noncoding RNAs, found in many eukaryotes, with their proteinaceous counterparts, showing that miRNAs share many similar activities but also display unique traits in their compartmentalization, rapid reversibility, and evolvability. Makeyev and Maniatis (p. 1789) provide examples of the profound systemwide influence that miRNAs can have on gene expression programs. miRNAs are also being linked to a growing list of common ailments, including cancer, heart disease, diabetes, and viral illnesses such as hepatitis. In a related News story (p. 1782), Jennifer Couzin explores how miRNAs are attracting the interest of biomedical researchers and biotechnology companies eager for new ways to diagnose and treat diseases.

In this video introduction, Perspective author John Mattick, Stephen Buratowski, and Science editor Guy Riddihough discuss the new and increasing understanding of how RNA regulates DNA, and how RNA may have been the original molecule of life.

Another recently discovered RNA-based regulatory system is the riboswitch, found in plant, fungal, and prokaryotic RNAs. Although they possess a deceptively simple bipartite structure, Breaker (p. 1795) describes how their chemistry, conformation, and kinetics have facilitated the evolution of sophisticated gene-control systems. Indeed, the overwhelming regulatory potential of RNA is graphically described by Amaral et al. (p. 1787), who list the many and varied instances in which RNA has been implicated in regulatory events.

This is not to suggest that research on transcription factors is moribund—far from it, as revealed by Core and Lis (p. 1791), for example, who discuss the revival of earlier work revealing a critical regulatory step, the pausing of the RNA polymerase II molecule, during the early phase of transcription elongation. The often highly dispersed nature of transcription factor binding sites in many eukaryotic genes provided the first clues that the spatial organization of the genome can be critical for gene regulation; for example, allowing combinatorial interactions between genes and regulatory elements, as described by Dekker (p. 1793). Understanding the origins of these regulatory systems requires that we examine how they have evolved, prompting Tuch et al. (p. 1797) to note that orthologous regulatory circuits with similar transcriptional outputs can nonetheless undergo massive rewiring in even closely related species.

Several gene regulatory systems are also highlighted in our online sister journal Science Signaling ( how oncogenic Ras causes the epigenetic silencing of Fas and other tumor-suppressor genes, how intrachromosomal looping positions enhancers close to the promoter of the tumor necrosis factor-αgene to stimulate its expression in activated T cells, and how the abundance of the transcriptional coactivator steroid receptor coactivator-3 controls estrogen-dependent gene transcription.

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