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New finding reveals battle behind our genes

The complex process regulating how genes are turned on and off is often compared to following a recipe. Miss a genetic ingredient, or add it in the wrong order — you could have a disaster.

New research from Stowers Institute for Medical Research in Kansas City, Missouri, suggests the process appears more like a battle between two opposing genetic forces than a step by step assembly of ingredients.

In their report, published in Genome Research, researchers examined regions of fruit fly DNA — called enhancers — which increased the likelihood of gene expression, which is the process of turning genes on or off. When a gene is turned on or off is crucial to formation of specific cell types such as nerves, skin and bone.

But a duel comes first. Stowers Associate Investigator Julia Zeitlinger PhD, and Postdoctoral Research Associate Nina Koenecke PhD, discovered DNA enhancers are engaged in an ongoing contest between gene activation (turning on) and gene repression (turning off). This contest creates a different epigenetic state for the histone proteins that DNA wraps around.

Activation sparks acetyl groups to become added to histones. Acetyl groups loosen the tight grip of DNA enhancers, which allows genes 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," Zeitlinger adds.

Enhancer activation, turning on, and repression, turning off, are known to occur both in the fruit fly Drosophila melanogaster as well as in mammals. But repression is much less studied in mammals.

This finding, therefore, clarifies the often misunderstood role of repression of DNA enhancers. It underscores the importance of the enhancer as an action, not an inaction. Typically, activation gets the most credit for gene expression. For example, enhancers that are epigenetically modified, although still inactive, were thought to be "poised" for future action. However, this new evidence suggests "poised" enhancers — do not lack a key ingredient for activation, but are simply turned off.

This study focused on enhancers of genes that are important to the fruit fly body plan. Zeitlinger and her colleagues drew on knowledge from diverse sources — developmental genetics and its analyses of DNA enhancers, mechanistic studies of histone modifications, and insights from global genomics analyses using next-generation sequencing — to develop a unifying model of how DNA enhancers work.

They also used ChIP-seq analysis to generate high-resolution maps of DNA enhancers under different conditions. Zeitlinger's long-term goal is to map and understand DNA enhancers even more as 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.

Gene expression is the process of turning genes on or off, and it's essential for creating specialized cells in the body.

Stowers research examined regions of fruit fly DNA called enhancers, which increase the likelihood of gene expression.

Such insight could increase understanding in diseases and developmental disorders caused by DNA enhancer mutations, giving a glimpse into the genetic forces contributing to human evolution.

Histone modifications are frequently used as markers for enhancer states, but how to interpret enhancer states in the context of embryonic development is not clear. The poised enhancer signature, involving H3K4me1 and low levels of H3K27ac, has been reported to mark inactive enhancers that are poised for future activation. however, future activation is not always boaserved and alternative reasons for the future activation. however, future activation is not always observed and alternative reasons for the widespread occurrence of this enhancer signature have not been investigated. By analyzing enhancers during dorsal-ventral (DV) axis formation in the Drosophila embryo, we find that the poised enhancer signature is specifically generated during patterning in the tissue where the enhancers are not induced, including at enhancers that are known to be repressed by a transcriptional repressor. These results suggest that, rather than serving exclusively as an intermediate step before future activation, the poised enhancer state may be a mark for spatial regulation during tissue patterning. We discuss the possibility that the poised enhancer state is more generally the result of repression by transcriptional repressors.

Other Stowers contributors include Jeff Johnston, Qiye He, Ph.D., and Samuel Meier.

The work was funded by the Stowers Institute for Medical Research and a New Innovator Award from the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

About the Stowers Institute for Medical Research
The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife, Virginia, opened the Institute in 2000. Currently, the Institute is home to about 500 researchers and support personnel, over 20 independent research programs, and more than a dozen technology development and core facilities. Learn more about the Institute at http://www.stowers.org and about its graduate program at http://www.stowers.org/gradschool.

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Dec 22, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Model shows that "poised" enhancer proteins are active specifically to affect tissue patterns of the fruit fly.
Cells become positioned as either Dorsal (TOP) or Ventral (BOTTOM) cell layers during development.
Image Credit: Stowers Institute for Medical Research, Kansas City, Missouri.



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