Driving a car with your feet on the gas pedal and the brake is not the most efficient way to get around town, but it is one way to control the speed of the car. According to NIEHS scientists, this scenario is exactly what happens when short DNA segments, known as enhancers, occur within genes, rather than being located outside of genes.
Why does the position of an enhancer matter? Before this research, most scientists thought enhancers only boosted the transcription — the first step in protein production — of their target genes. This work suggests enhancers that are within a host gene also dampen the transcription of that gene, which means less protein is produced. Raja Jothi, Ph.D., head of the NIEHS Systems Biology Group, and his team showed that deletion of such enhancers increases the expression, or protein production, of the host gene and can alter cell fate.
For example, having less of a protein that prevents tumor growth may mean that a person is more prone to developing cancer. By contrast, deleting an enhancer from within a known cancer-causing gene could have the same result, because removing the brake activates the gene.
"We know that enhancer mutations are associated with many types of cancer," said Jothi, who is the corresponding author of the Molecular Cell article. "We need to determine whether any of the cancer cases involve activation of a cancer-causing gene due to loss of the enhancer-mediated suppression function."
Pengyi Yang, Ph.D., did much of the groundwork for this study by mining and analyzing published genomic and transcriptomic data on embryonic stem cells. Yang is a former research fellow in Jothi’s group who is now an independent researcher at the University of Sydney, Australia.
He explained that gene transcription is a highly regulated process that involves many factors, including an enzyme called RNA polymerase II (Pol II). Pol II turns DNA into messenger RNAs, which are eventually synthesized into functional proteins.
Other researchers have found that Pol II also transcribes enhancer DNA, but it was Senthilkumar Cinghu, Ph.D., a visiting fellow in Jothi’s group, and the rest of the Jothi’s team who showed that Pol II transcription of enhancers within genes, also known as intragenic enhancers, interferes with and lessens the transcription of the host gene.
"When you have an enhancer within a gene and both are being transcribed by their respective Pol IIs at the same time, you have a situation similar to two trains travelling toward each other on the same track," Cinghu said. "The trains will likely collide and go off the tracks, with neither of them making it to their destinations."
Breaking new ground
Jothi said the discovery of an unanticipated role for enhancers will break new ground in the field of transcription and alter the conventional view of enhancers as transcriptional activators. The findings have been highlighted in Nature Reviews Genetics and Nature Reviews Molecular Cell Biology. Researchers within NIEHS are also taking notice.
Paul Wade, Ph.D., Deputy Chief of the NIEHS Epigenetics and Stem Cell Biology Laboratory, was not involved in the research, but remembers when Jothi found an accumulation of Pol II in unexpected places in some genes a few years ago.
"Raja observed that enhancers located within genes set up a collision between polymerases, and that this collision regulates expression of a gene in a novel way," Wade said. "His attention to a peculiar detail in published data, something that the rest of the field ignored, has led to this really nice finding."
Citation: Cinghu S, Yang P, Kosak JP, Conway AE, Kumar D, Oldfield AJ, Adelman K, Jothi R. 2017. Intragenic enhancers attenuate host gene expression. Mol Cell 68(1):104−117.e6.
Wrighton KH. 2017. Transcription: intragenic enhancers dampen gene expression. Nat Rev Genet; doi:10.1038/nrg.2017.90 [Online 24 Oct. 2017].
Wrighton KH. 2017. Transcription: intragenic enhancers dampen gene expression. Nat Rev Mol Cell Biol; doi:10.1038/nrm.2017.111 [Online 25 Oct. 2017].