"enhanceosome"
11. ON THE CONTROL OF GENE EXPRESSION
From 31May ScienceWeek
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A.H. Brivanlou and J.E. Darnell Jr. (Rockefeller University, US)
discuss the control of gene expression, the authors making the
following points:
1) All cellular life can recognize and properly respond to
molecules in the extracellular environment. Indeed, an increased
repertoire of recognized extracellular signaling molecules
matched with increasingly sophisticated intracellular responses
was the central requirement for the evolution of metazoan life.
Two very broad fields of research, which are often described as
"signal transduction" and "control of gene expression," have
merged recently to become a pivotal arena for developmental
genetics as well as cellular biochemistry.
2) A host of proteins crucial to transcription initiation are
assembled into the RNA polymerase, the general transcription
factors, coactivators, corepressors, chromatin remodelers,
histone acetylases, deacetylases, kinases, and methylases, to
list the main participants (1-5). These crucial proteins are
present in all eukaryotic cells and contribute to the initiation
of every RNA polymerase II primary transcript that eventually
becomes messenger RNA.
3) As important as the approximately 200 to 300 proteins that
constitute the coactivators and the transcriptional machinery
may be to the survival of cells and organisms, the regulation of
the choice of specific initiation sites for transcription is not
vested in these proteins. Rather, transcriptional regulation
depends on members of an even larger number of proteins, in
mammals perhaps 2000 to 3000, with two characteristic domains: a
DNA binding domain that binds gene-specific regulatory sites
directly, and a second domain that exhibits transcriptional
activation potential. In some cases this dual requirement is
shared between partner proteins, so that the site-specific
binding domain and transcription activation domain occur on
separate proteins. These site-specific transcription factors
recruit coactivators and the transcription machinery to initiate
gene-specific transcription (1-5). As development and cell
specialization occurs, selection among these 2000+ transcription
factors for the regulation of cell-specific gene expression
involves (i) a cascade of transcriptional control of
transcription factor genes, and (ii) signals from outside the
cell that activate, posttranscriptionally, already formed
transcription factors. In the regulatory regions in the DNA of a
few well-studied vertebrate genes, as many as six to eight
different protein chains, acting on one enhancer (together
forming an "enhanceosome"), are required for gene-specific
regulation, and this is likely true for many other genes. The
combinatorial use of subsets of the 2000+ proteins could easily
mean that the complete set of regulators for each gene is
unique, ensuring the right amount of the right protein at the
right time as development proceeds.
References (abridged):
1. S. Malik and R. G. Roeder, Trends Biochem. Sci. 25, 277 (2000)
2. A. M. Naar, B. D. Lemon, R. Tjian, Annu. Rev. Biochem. 70,
475 (2001)
3. A. M. Naar, S. Ryu, R. Tjian, Cold Spring Harbor Symp. Quant.
Biol. 63, 189 (1998)
4. K. A. Jones and J. T. Kadonaga, Genes Dev. 14, 1992 (2000)
5. T. Jenuwein and C. D. Allis, Science 293, 1074 (2001)
Science 2002 295:813
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