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Researchers reveal secrets of alternative splicing

by Ruth SoRelle, MPH

Bert O'Malley, MD

For decades, the dictum for those studying the action of genes was 'one gene, one protein' – meaning each gene makes one protein.

It was a logical assumption, but when the human genome was finally sequenced in a heroic international effort in the 1990s, researchers found fewer than 30,000 human genes. Obviously, somehow, they were responsible for giving the instructions that resulted in production of more than 120,000 proteins. The cellular 'recipe' had to be alterable in some way.

Process of alternative splicing

Alternative splicing, a way in the genetic 'code' from which proteins are assembled is altered, is one answer as to how this phenomenon occurs. Now, researchers at Baylor College of Medicine think they have found how this process is controlled.

'There is a lot of information in a gene,' said Bert O'Malley, MD, chair of the BCM department of molecular and cellular biology and principal author of a report on the topic that appeared in a recent issue of the journal Molecular Cell. The cell, he said, makes one protein using some of the information in a gene and another protein using different information from the same gene.

In other words, if the information in a gene is like the elements of a computer code, leaving out some of the code results in a very different program than what would have resulted if all the components had been included or different parts had been left out. In this instance, leaving out part of the gene changes the protein.

'How do they decide to do that?' he said. 'We know that at different times during development of an organism, in different tissues and in different hormonal states, the gene makes different proteins. The question is how is this controlled? Is there some underlying mediator of this action that we do not now about?'

Estrogen and progesterone

Steroid hormones, he said, can do this in some instances. These hormones include among their numbers estrogen and progesterone.

'When they act on their target genes, they can change the amounts of one protein versus another protein that are made from (information coded in) a single gene.'

When hormone binds to receptors inside the cells, they are activated to seek out target genes.

'That's step one,' said O'Malley. 'Step two is recruiting additional proteins that get the gene expressed and transcribed.'

A gene is expressed when the message it carries in its DNA is expressed as a trait of an organism – i.e., the gene for fur color shows up in the brown coat of a mouse. Transcription involves the translation of the message carried in the DNA into something that can be read by the cell.

Co-activators

The additional proteins to which O'Malley refers are the co-activators who are the stars of the Molecular Cell paper. These coactivators –CAPERα and CAPERβ –are critical to the process.

These coactivators not only cause the gene to begin the process that results in protein production, they also determine what kind of RNA (a kind of genetic template for the protein) is made as well as what kind of protein results.

'This subgroup of coactivators, when brought to the gene, can enhance the amount of RNA made off the gene or the quantitative expression of that gene as well as qualitatively change what comes off the gene in terms of what protein is made,' said O'Malley.

These coactivators are unusual in that they can both control alternative splicing that results in different proteins being made as well as the production of RNA.

'It is not just changes in the amount of RNA made or changes in a lot of other little things you could imagine, but they actually recruit a subclass of proteins (the coactivators) that when brought to the gene can enhance the amount of RNA made off a gene or the quantitative expression as well as qualitatively change what comes off the gene in terms of the protein that is made,' he said.

Manipulating the process at the molecular level, O'Malley and his colleagues showed that the proteins have evolved as dual control proteins that both mediate the amount of RNA made as well as which protein results.

Others who participated in the research include Drs. Susan M. Berget, Dennis H. Dowhan, Eugene P. Hong, Didier Auboeuf, Andrew P. Dennis and Michelle M. Wilson of the BCM departments of molecular and cellular biology and biochemistry and molecular biology.

The citation for the article: Mol Cell. 2005 Feb 4;17(3):429-39.

This research was supported by grants from the National Institutes of Health, the National Institutes of Child Health and Human Development, the National Institute of Diabetes, Digestive and Kidney Diseases and the Welch Foundation.

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