Scientists participating in the modENCORE study have the goal of understanding the causes of hereditary genetic diseases in humans

New discoveries about the interaction of genes and transcription factors in creating different types of RNA will be of interest to pathologists and clinical chemists performing genetic tests and molecular diagnostic assays in their medical laboratories.

The goal of this research is to better understand hereditary genetic disease in humans. The new knowledge is based on studies of the common fruit fly, or Drosophila melanogaster (D. Melanogaster), and to a lesser extent a tiny worm Caenorhabditis elegans (C. elegans). Both have been used as research models to study the human condition.

Research Could Give Pathologists New Diagnostic Tools

Now these species are helping scientists figure out how to insert DNA sequences back into a person and activate histones and other yet-to-be-discovered switches to cure genetic diseases like cystic fibrosis. (Also see Dark Daily, “New Study of Fruit Fly Genome Reveals Complexity of RNA and Provides a Model for Studying Mechanisms for Hereditary Diseases in Humans, July 7, 2014.)

The common fruit fly (pictured above) has been used as a model organism for studying the human condition since the early 1900s. Because much of its genetic mechanisms are similar to humans, studies of the fruit fly are helping scientists understand how to control genetic activity in people that plays a role in inherited genetic diseases. (Photo copyright University of Washington.)

The common fruit fly (pictured above) has been used as a model organism for studying the human condition since the early 1900s. Because much of its genetic mechanisms are similar to humans, studies of the fruit fly are helping scientists understand how to control genetic activity in people that plays a role in inherited genetic diseases. (Photo copyright University of Washington.)

This innovative research is being done by scientists involved in the National Human Genome Research Institute’s (NHGRI) international modENCODE, (model organism ENCyclopedia Of DNA Elements) project. The researchers are using fruit flies and worms to study mechanisms of different types of cells in humans, like neuron, blood and liver cells.

In experiments with these species the researchers cataloged the parts of the genome used by cells as fruit flies and worms develop from eggs to adult animals. They also mapped the histone marks and located the transcription factors binding with the DNA.

modENCORE Scientists Discover Key to Switching On Dormant Genes

Cellular DNA is coiled around spool-shaped histones, the chief protein components of chromatin. Chromatin plays a role in gene regulation, or gene expression. Both processes use various mechanisms to increase or decrease production of specific gene products—including proteins and Ribonucleic acid (RNA)—at different points in an organism’s lifetime.

When DNA is hidden in this manner, gene-reading molecules cannot read it, explained a story published by New York Times. But exposing the gene causes a transcription factor protein to enlist other molecules to read it and produce a new protein or RNA molecule.

Researchers have learned that this may cause a single transcription factor to switch on dozens of other genes. Sometimes those genes encode transcription factors of their own that enable a cell to immediately produce hundreds of different molecules.

Comparing Genetic Processes in Humans, Fruit Flies, and Worms

Using the same methods to gather data on humans, the researchers compared the three species—humans, fruit flies, and worms—on a scale never before attempted, noted the New York Times report. Despite the tremendous differences on the evolutionary tree between the three species, researchers found remarkable parallels in the workings of their DNA. All three species use many similar molecular strategies to control cell growth, development, and function, explained the researcher, noting that the three species turn genes on and off in a similar pattern with a predictable rhythm.

“If features of the genomes of these very disparate organisms are the same, it is likely those features are very important and fundamental to cell function,” commented modENCORE researcher Robert H. Waterston, M.D., Ph.D., in an article published by UW Health Sciences NewsBeat. He is Professor and Chair of Department of Genome Sciences at the University of Washington School of Medicine (UW).

Waterson co-authored three of the five papers on this study that were published in the August 28, 2014, edition of the journal Nature.

Sets of Genes That Work Together Were Identified

Researchers found 16 sets of genes, each with hundreds of genes working together. Although there is still much to understand about the functions these genes are performing in the three species, the scientists did observe dozens of clusters of genes that were exceptionally active at various stages of development in both the worm and fruit fly. They suggested that these genes could be essential in transforming an egg into an adult animal.

“That these clusters appear across species suggests that they are very ancient,” Waterston observed. “Organisms don’t generally reinvent the wheel.”

Robert H. Waterston, M.D., Ph.D. (pictured above), Chair of the Department of Genome Sciences at the University of Washington School of Medicine, is a member of the modENCORE research team that developed a predictive animal model to study how to insert DNA sequences back into a person’s genes and activate histones and other switches to cure genetic diseases. He co-authored three of five papers on this study that appeared in the journal Nature. (Photo copyright University of Washington.)

Robert H. Waterston, M.D., Ph.D. (pictured above), Chair of the Department of Genome Sciences at the University of Washington School of Medicine, is a member of the modENCORE research team that developed a predictive animal model to study how to insert DNA sequences back into a person’s genes and activate histones and other switches to cure genetic diseases. He co-authored three of five papers on this study that appeared in the journal Nature. (Photo copyright University of Washington.)

Histone Marks Offer Similar DNA Control in Flies, Worms, and Humans

Another relevant finding by the research team was that histone marks control DNA in a similar manner in all three species. When certain marks were present around a gene, the scientists could predict its activity level, regardless of whether the specie was a worm, fruit fly, or human. These similarities could reveal a lot about how the cacophony of human genes lead to diseases.

“The neat thing is that it works—it really works well,” stated Mark Gerstein, Ph.D., a Professor at Yale University and project investigator, in speaking about the modENCORE team’s predictive model in the New York Times report.

Three Species Followed Some of the Same Gene Regulation Rules

Researchers observed that transcription factors grabbed onto genes in complex patterns that bedazzled them. But beneath this complexity, all three species followed some of the same rules for regulating genes, noted Michael Snyder, Ph.D., another member of the modENCORE team, in the New York Times piece. He is a Professor and Chair of the Genetics Department at Stanford School of Medicine, and Director of the Stanford Center of Genomics and Personalized Medicine.

Scientist Michael Snyder, Ph.D. (pictured above),is another modENCORE researcher who is Genetics Professor at Stanford University and Director of the Stanford School of Medicine’s Center of Genomics and Personalized Medicine. Snyder says that, despite the complexity of gene transcription patterns, encoding of genes in all three species follows similar rules. (Photo copyright Stanford University.)

Scientist Michael Snyder, Ph.D. (pictured above),is another modENCORE researcher who is Genetics Professor at Stanford University and Director of the Stanford School of Medicine’s Center of Genomics and Personalized Medicine. Snyder says that, despite the complexity of gene transcription patterns, encoding of genes in all three species follows similar rules. (Photo copyright Stanford University.)

Snyder pointed out that many transcription factors work in distinctive patterns. Gene A, for example, encodes a factor that switches on gene B, and B, in turn, switches on gene C. This pattern, which is known as “feed-forward loop,” may be a useful way to identify fast, predictable changes in gene activity, like when a stem cell irreversibly transforms into a blood cell, explained Snyder. “You setup a system that says, ‘Go!’”

Study Expands Understanding of Disease-Causing Gene Mechanisms  

“The potential of such data is enormous,” commented Alexander Stark, Ph.D., a Bioinformatician and Group-leader at the Research Institute of Molecular Pathology (IMP), a nonprofit, biomedical research institute in Vienna, Austria, in the New York Times story. He cautioned, however, that there is still much to be learned about how genes act in all three animal species. For example, histones may leave a gene silent when it is expected to be active. Stark is not a member of the modENCORE team.

The work of these researchers may give molecular pathologists and molecular clinical chemists new tools for diagnosing gene-related diseases. Traditionally, researchers have focused on gene mutations as the sources of diseases. However, an increasing number of studies indicate that abnormal activity in a normal gene can trigger onset of a disease. As Snyder pointed out, “If they’re [the genes] not active or if they’re hyperactive in a cell, maybe that’s driving a disease.”

Pathologists May Use This Research to Develop New Medical Lab Tests

From this perspective, the work of the modENCORE team is providing an important, but preliminary, understanding of how gene mechanisms could prevent or cure diseases by turning on or off gene activity. Further developments in this area, as confirmed by other researchers, may result in new ways for pathologists and clinical laboratory professionals to evaluate the processes active in DNA and RNA as a way to more accurately detect and understand genetic processes that contribute to human diseases.

—Patricia Kirk

Related Information:

Tiny, Vast Windows Into Human DNA

Diversity and dynamics of the Drosophila transcriptome

Regulatory analysis of the C. elegans genome with spatiotemporal resolution

Genomics: Hiding in plain sight

Comparative analysis of metazoan chromatin organization

Comparative analysis of regulatory information and circuits across distant species