Freedom of Expression

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.
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 (www.sciencemag.org/generegulation/): 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�a gene 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.
�GUY RIDDIHOUGH, BEVERLY A. PURNELL, JOHN TRAVIS