How are human genes regulated? Although the proteins that read the gene regulatory code, transcription factors (TFs), have been largely identified, it is not well known which sequences TFs can recognize. A new study identifies DNA sequences that bind to over 400 TFs. This knowledge is required to understand how differences in genomes of individuals affect their risk to develop disease, according to researchers at Karolinska Institutet in Sweden.

“The genome is like a book written in a foreign language—we know the letters but cannot understand why a human genome makes a human or the mouse genome a mouse,” says Jussi Taipale, Ph.D., who led the study at the department of biosciences and nutrition. “Why some individuals have higher risk to develop common diseases such as heart disease or cancer has been even less understood.”

The scientists note that the human genome encodes approximately 1,000 transcription factors, which bind specifically to short sequences of DNA and control the production of other proteins. Using high-throughput SELEX and ChIP sequencing, the team describes DNA sequences that bind to over 400 TFs.

The team compared binding specificities of human transcription factors to those of the mouse. Surprisingly, no differences were found. According to the scientists, these results suggest that the basic machinery of gene expression is similar in humans and mice, and that the differences in size and shape are caused not by differences in transcription factor proteins, but by presence or absence of the specific sequences that bind to them. In addition, global analysis of the data revealed that homodimer orientation and spacing preferences, and base-stacking interactions, have a larger role in TF-DNA binding than previously believed.

“Taken together, the work represents a large step toward deciphering the code that controls gene expression, and provides an invaluable resource to further understand the function of the whole human genome,” says Dr. Taipale. “The resulting increase in our ability to read the genome will also improve our ability to translate the rapidly accumulating genomic information to medical benefits.”

The study was published yesterday in the journal Cell in a paper titled “DNA-Binding Specificities of Human Transcription Factors”.

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