Scientists from the Stowers Institute for Medical Research report that the process of gene expression may be more like a battle between two opposing genetic forces rather than a stepwise assembly of ingredients.
In their study (“Drosophila Poised Enhancers Are Generated during Tissue Patterning with the Help of Repression”), published online in Genome Research, the researchers examined fruit fly enhancers, which increase the likelihood of gene expression. Associate Investigator Julia Zeitlinger, Ph.D., and postdoctoral research associate Nina Koenecke, Ph.D., discovered that DNA enhancers engage in an ongoing contest between activation and repression, which results in a different epigenetic state of the histone proteins around which DNA is wrapped. Activation sparks the addition of acetyl groups to histones, which in turn loosen their grip on DNA enhancers, allowing them to be switched on. Repression, on the other hand, removes this acetylation mark and prevents the switch from ever being flipped.
“Through this balance between forces you can shift an enhancer more easily from inactivity to activity,” Dr. Zeitlinger says.
Enhancer activation and repression are known to occur both in the fruit fly Drosophila melanogaster and in mammals. But repression is much less studied in mammals.
The finding therefore clarifies the often misunderstood role of repression in DNA enhancers and underscores its importance as an action, and not just an inaction. Typically, activation gets the most credit for its role in gene expression. For example, enhancers that are epigenetically modified but still inactive have been thought to be “poised” for future action. However, this new evidence suggests that “poised” enhancers, rather than lacking a key ingredient for activation, may be repressed.
“When there is an opposition between the two enzymes responsible for acetylation state, it creates an ultrasensitivity under some conditions,” notes Dr. Zeitlinger. “With just a little more activation, this can create a very dramatic switch in the enhancer's activity. This mechanism could allow a gene being turned on in some cells, while turned off in other cells of the body.”
In this study, which focused on enhancers of genes important for specifying the fruit fly body plan, Dr. Zeitlinger and her colleagues drew on knowledge from diverse sources (developmental genetics and its mechanistic analyses of DNA enhancers, mechanistic studies on histone modifications, and insights from global genomics analyses using next-generation sequencing) to develop their unifying model of how DNA enhancers work. They used chromatin immunoprecipitation-sequencing (ChIP-seq) analysis to generate high-resolution maps of DNA enhancers under different conditions.
The team's long-term goal is to map and understand DNA enhancers more extensively. There are hundreds of thousands of enhancers in the human genome. Such insight could provide understanding into diseases and developmental disorders caused by DNA enhancer mutations and give us a glimpse into the genetic forces that have contributed to human evolution.