THERE鈥橲 a particularly embarrassing gap in our knowledge of genes鈥攚e
don鈥檛 know exactly how they turn on and off. 鈥淭he most fascinating questions
still remain,鈥� says Robert Tjian, a biochemist at the University of California,
Berkeley. Finding out what flicks the switch and regulates gene expression could
open new avenues for attacking almost every illness.
A gene is said to be switched on when it is being transcribed, producing a
strand of RNA that a ribosome translates into protein. The grunt work of
transcription falls to an enzyme complex called RNA polymerase, which must unzip
the DNA鈥檚 double helix, read its sequence and snap the building blocks of RNA
together one after the other, like a machine laying a railroad track.
But how does RNA polymerase know which genes to transcribe? In 1982, Tjian鈥檚
group found a clue in the shape of the first human 鈥渢ranscription factor鈥�. Sp1,
as they called it, latches onto DNA at a binding site with a unique sequence:
GGGCGG. Other transcription factors were soon discovered that bind to other
sequences.
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It turns out that Sp1 is just the first of a huge cast of characters that
help RNA polymerase do its job. What each protein does is still uncertain, but
Tjian likens the process to building a car. First, proteins such as Sp1 outline
a work area at the start of a gene, where the rest of the transcription team
gathers. These factors begin by getting other proteins to loosen the tight
packing around the DNA. 鈥淏efore you even begin to build the car, you鈥檝e got to
open the garage door,鈥� Tjian says.
Then a team of molecular mechanics, called the TFIID complex, wheels RNA
polymerase to the start of the gene, while yet other proteins called TAFs form a
chain of communication between Sp1, its helpers and the polymerase itself. Then
RNA polymerase heads down the gene, transcribing all the way.
Biologists estimate that up to 10 000 of the 100 000 proteins that our genes
encode play a role in these transcription complexes. To get at the intricate
wiring of a human cell鈥檚 gene-control network, researchers are now turning to
DNA chips, which can monitor the activity of thousands of genes
simultaneously.
Using these chips, Tjian鈥檚 team has found that a single transcription factor
can affect different genes in different ways. They monitored 6500 genes in cells
producing various mutant forms of a TAF known as TAFII250. Some of those genes
lost or gained activity when part of TAFII250 was obliterated. When a different
region of the protein was knocked out, the activity of a completely different
set of genes was affected (Proceedings of the National Academy of
Sciences, vol 97, p 2456). 鈥淧lay this game with 500 different transcription
factors,鈥� Tjian says, 鈥渁nd you鈥檒l get a pretty good idea of how these networks
颈苍迟别谤补肠迟.鈥�