Wednesday, August 26, 2009

Transcription Factors

As I blogged previously, biological systems often do one thing in many ways. Nowhere is this clearer than genetic regulation, the vital process--er, processes--by which the activity of genes changes in response to conditions.

By far the best-known way that gene activity is regulated is by binding of a protein, called a transcription factor, to a nearby region of DNA. Its presence speeds or slows the transcription of the DNA sequence into the complementary sequence in messenger RNA, which is then translated into biologically active protein.

For example, the bound transcription factor can slow transcription by blocking access to the DNA by the RNA polymerase enzyme that does the transcription. Alternatively, it can attract the enzyme, make transcription more likely.

The first known example of genetic regulation, which controls digestion of lactose by the bacterium E. coli, uses these basic ingredients. The details have been clarified on many levels, ranging from the atomic interaction of the proteins with the DNA double helix to the differential equations that describe it. Mark Ptashne described these levels in his dense but wonderful 1986 book A Genetic Switch, last updated in 2004 (Amazon, B&N).

The transcription-factor mechanism for gene regulation is easy to grasp because it doesn't challenge the simplest view of gene activity: DNA is transcribed to RNA, which is translated to protein. In this mechanism, the control arises when the last step of this chain, a protein, modifies the beginning of the chain, transcription. Moreover, this mechanism has all the ingredients needed for positive or negative feedback, leading to homeostasis, oscillations, hysteresis, and other, more complex dynamical behavior.

But human cells have several thousand transcription factors, perhaps 10% of the total number of proteins. Also, some transcription factors affect many different genes. One of the many computation-intensive tasks for modern biologists is finding all possible target genes of a transcription factor by combing through gigabytes of genome data.

A real cell, then, contains a complex network of tens of thousands of genes, which code for proteins, many of which go on to modify the activity of their own or other genes. Building and exploring mathematical models of these complex networks is the continuing goal of systems biology, which I've written about extensively, for example at the New York Academy of Sciences (see my Clips for details). A critical tool for learning about the networks is microarrays, which simultaneously measure thousands of messenger RNA levels.

But wait, there's more!

In eukaryotes like ourselves, DNA must be unpacked from tightly-wound spools for transcription, which is done by a complex of many proteins that interact with RNA polymerase and the transcription factors. The resulting RNA is processed to splice out some sections, and is chemically labeled and exported from the nucleus. Once in the body of the cell, the RNA needs to escape degradation and get to a ribosome where it may be translated. Finally, the resulting protein is chemically modified both during production and afterwards, and must be imported into the nucleus if it is to affect transcription.

Essentially every one of these steps--not just transcription --is regulated. In particular, over the past decade or so, researchers have found that other short RNA segments in the cell act (in conjunction with proteins) to modify the production and translation of messenger RNA. Many of these mechanisms are the subject of active research, and I will describe some of them in future posts.

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