Scientists Explain How Transcription Factors Know Which Genes to Turn On

A fundamental problem in biology is how genes are turned on and off during development and in response to environmental stress. The activity of genes is regulated by protein molecules called transcription factors, which bind to DNA. Richard S. Mann, PhD, and colleagues have solved the longstanding puzzle of why a single transcription factor can turn on many genes in a test tube, but only a few genes in a live organism.

Mann and his team, in collaboration with biological sciences professor Harmen Bussemaker, PhD, found that when transcription factors associate with protein cofactors present in living cells, the cofactors increase the specificity of DNA binding. New high-throughput methods to analyze the complete repertoire of transcription factor binding sites allowed the researchers to show that, by itself, a transcription factor can bind to many genes, but when it associates with a cofactor, its binding is much more restricted due to a higher degree of specificity.

The work also shows that the 3-dimensional structure of both the DNA and the protein plays a critical role in specificity. New methods, which analyze the 3-dimensional shapes of DNA sequences, were devised by coauthors Remo Rohs, PhD, now at the University of Southern California, and Barry Honig, PhD, also at Columbia. The findings show that the addition of structural information greatly increases the ability to understand transcription factor specificity.

“Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins” was published in Cell on December 9, 2011.