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Transcription Factor Binding Differences Detected in Humans, Yeast

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Transcription factor binding patterns across the genome vary from one individual to the next, according to a paper in the early, online version of Science today.

Using sequencing coupled with chromatin immunoprecipitation, a Yale University and Stanford University-led research team assessed transcription factor binding patterns in 10 humans from three ancestries and one chimpanzee. Together, their results suggest that transcription factor binding varies both within and between species — largely owing to SNPs and structural variants.

"These binding regions, or chunks, vary among individuals," senior author Michael Snyder, formerly at Yale and now genetics chair at Stanford, said in a statement, "and they have a profound impact on gene expression."

Snyder and his colleagues used ChIP-Seq to map RNA Polymerase II and NF-kappaB binding patterns in lymphoblastoid cell lines generated from ten individuals' blood samples: five individuals of European ancestry, three individuals of Nigerian ancestry, and two individuals of Asian ancestry.

Overall, the team found more than 19,000 RNA PolII- and about 15,500 NF-kappaB-binding regions.

While the peaks of these sites tended to fall around the same spot in the genome in various individuals, the degree of binding varied at these sites.

In addition, roughly a quarter of the RNA PolII binding sites varied from one individual to the next — as did about 7.5 percent of the NF-kappaB sites. The variability was even higher in intergenic regions (more than 1,000 bases from transcription start sites).

What's more, subtle differences in the binding of these factors tended to coincide with one another, the researchers noted, suggesting "adjacent binding sites and [binding regions] may influence one another, perhaps through cooperative binding or interactions with other proteins."

By integrating SNP data from the 1000 Genomes Project, the researchers found that binding regions with significantly different binding patterns coincided with SNPs — particularly for NF-kappaB binding regions.

The team also looked at the effects of variants within specific DNA motifs and used what they dubbed the "Allele Binding Cooperativity" test to assess shared associations between motifs exhibiting variable binding.

Using new and previously published data on structural variation in the genome, the researchers found that structural variants also increased the frequency of binding site differences between individuals.

Meanwhile, the team's RNA-sequencing data illustrated how binding site differences in each cell line affected gene expression. They found that most — but not all — binding site differences corresponded to gene expression differences.

But population-specific binding region differences seem to be fairly rare, the researchers noted. When they compared binding and expression patterns in individuals from each ancestral background, they found that just 0.1 to 0.4 percent of these events were population specific.

In contrast, their human-chimpanzee comparisons revealed differences at 32 percent of binding regions tested. Again, these differences were more pronounced in intergenic binding sites and tended to coincide with polymorphisms.

Taken together, those involved in the study say such findings are consistent with a role for genetic variant-related differences in transcription factor binding that leads to gene expression differences between individuals and, consequently, variation within humans.

"Overall, our data demonstrate extensive contributions of genetic variations on [transcription factor] binding, many of which are expected to be functional through their affect on gene expression," the researchers concluded.

And because such differences "greatly exceed estimates for sequence variation in coding sequences," they added, the results suggest "a strong role for binding variation in human diversity."

Variable transcription factor binding also occurs in yeast, the team reported online yesterday in Nature. For that study, they used ChIP-Seq to explore differences in Ste12-binding between yeast cells and began identifying loci influencing this variability.

"Together these two studies tell us a lot about the so-called regulatory code that controls variation among individuals," Synder said in a statement.

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