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Differences in Transcription Factor Binding May Explain Many Human Differences

Differences in gene expression associated with differences in transcription factor binding may help explain many of the differences among individual humans, according to a team of Yale University researchers and collaborators. Transcription factors bind to DNA regions and set in motion programs of increased or decreased gene expression through their influence on the binding of RNA polymerase and the transcription of DNA to RNA. Using the technique of chromatin immunoprecipitation followed by sequencing (ChIP-Seq), the authors showed, on a genome wide basis, that the binding regions for RNA polymerase II and NF-kappa B differed by 25 percent and 7.5 percent, respectively, between any two human individuals in samples of lymphoblastoid cells from 10 individuals of various ancestries. RNA polymerase II, which is active in all cells, transcribes DNA into RNA, and its activity is dependent on the appropriate transcription factors being present at the DNA binding regions. NF-kappa B is a transcription factor that is activated by stress, plays a key role in immune responses to infections, and has been implicated in several diseases, including cancer. Approximately 19,000 and 15,500 binding regions were found for RNA polymerase II and NF-kappa B, respectively, in the study. The researchers found that differences in the binding of RNA polymerase II and NF-kappa B at DNA regions were frequently associated with SNPs and genomic structural variants (SVs), such as duplications, deletions, and inversions of long stretches of DNA, and were often correlated with differences in gene expression, suggesting functional consequences of binding variation.

“We found that about one third of the differences in binding was caused by SNPs and structural variation,” said senior author Dr. Michael Snyder of Yale University (Dr. Snyder has since joined the faculty at Stanford University). “This is the first time anyone has shown that SNPs and structural variation affect large numbers of regulatory elements that control gene expression. Normally, people look at differences in the genes themselves rather than in the regulatory regions, because they are difficult to identify.”

The study also reported finding differences in the binding of RNA polymerase II and NF-kappa B near genes implicated in many major diseases, including type 1 diabetes, systemic lupus erythematosus, chronic lymphatic leukemia, schizophrenia, asthma, Crohn’s disease, and rheumatoid arthritis. “Variation in the regulation of genes might eventually help account for some of the varying susceptibility to diseases we see in the population,” said lead author Maya Kasowski.

In addition to looking at humans, the researchers examined transcription factor binding for a single chimpanzee. The study showed that 32 percent of RNA polymerase II binding regions differed between the humans in the study and the chimp. Dr. Snyder said that he included the chimp out of curiosity to see how transcription factor binding might account for differences between humans and chimps. But the 32 percent difference for RNA polymerase II binding between chimps and humans was not that much larger than the 25 percent difference in RNA polymerase II binding among any two human individuals.

Nevertheless, the differences between RNA polymerase II binding and NF-kappa B binding (25 percent and 7.5 percent, respectively) in humans and between RNA polymerase II binding in humans versus chimps (35 percent) far exceed the estimates for coding sequence variation between humans (0.025 percent) and between humans and chimps (0.71 percent), suggesting a strong role for transcription factor binding variation in human diversity, the researchers said.

According to the scientists, their results indicate that many differences in individuals and species occur at the level of transcription factor binding and provide insight into the genetic events responsible for these differences.

This report was published online on March 18 in Science Express. [Howard Hughes Medical Institute press release] [Yale University press release] [Science abstract]