Prominent researchers from around the world ” including Roger Kornberg, winner of the 2006 Nobel Prize for Chemistry ” gathered in San Diego at the Salk Institute Jan. 11-14 for a conference titled Diseases of Transcription.
Although transcription rarely makes headlines, it is one of the most important processes that occur in the body. Think of human genes as the list of ingredients for everything in the body. Transcription is the directions for how those ingredients are mixed together. Consider a loaf of bread and a croissant: they share many basic ingredients, such as flour, water, eggs and milk, but the important difference between making a loaf of bread and a croissant is how those ingredients are mixed. Transcription is the crucial first step of adding just the right amount of ingredients into the mix at just the right time and just the right place.
When transcription does not happen properly, when too much or too little of an ingredient is added or something is added at the wrong time or place, then diseases result, such as cancer, heart failure, diabetes and osteoporosis. At the Diseases of Transcription Symposium, scientists discussed their remarkable efforts to understand and treat these diseases.
The conference started with a keynote address by James E. Darnell, from the Rockefeller University. Dr. Darnell was involved in the first studies that revealed transcription is regulated; in other words, that the ingredients are indeed precisely measured out. Transcription is regulated by proteins known as “transcription factors.” Think of these transcription factors as the measuring cups that determine how much of each ingredient is added. Darnell presented research about how these transcription factors are modified to turn off transcription; how the measuring cups are told to stop adding ingredients, which is an integral part of ensuring that just the right amount of ingredients are added into the mix.
Several of the following presentations concerned “epigenetic” control of transcription. The DNA in human cells is tightly wound and packaged in order to save space. Epigenetic modifications determine how tightly packaged the DNA is, which in turn regulates whether or not the transcriptional machinery has access to DNA. Epigenetics can best be thought of as regulating whether or not the cells have access to the kitchen. If the kitchen door is closed, the cell does not have access to the ingredients and cannot even look at the cookbook.
Kornberg, from Stanford University, discussed some of the mechanisms behind the unwinding of DNA that allow transcription to begin. David Allis, also from the Rockefeller University, talked about the “histone code,” the signals attached to the DNA packaging proteins that regulate access to DNA. When this regulation of access to DNA is disrupted, diseases such as cancer can occur. Victoria Richon, from Merck Research Laboratories, described new drug treatments that target histone modifications in an attempt to rebalance epigenetic control and reduce tumor growth.
Nathaniel Heinztman, a graduate student at the University of California, San Diego (UCSD), talked about his research finding distant enhancers, regions of DNA that regulate transcription but are not located near the genes they regulate. The human genome is organized in a curious manner, in which some parts of the recipe are spread throughout the cookbook. For example, most of a recipe might be on page 12, but then one key step might be found on page 92. Heinztman’s work enables detection of these long-range acting enhancers by looking at signatures of epigenetic modifications.
Another active area of research in transcription is in “co-activators,” proteins that interact with transcription factors to dictate tissue-specific and temporal expression. Think of co-activators as hands that hold the measuring cups and cause the measuring cups to add ingredients at exactly the right time and place. These co-activators often form huge complexes involving several different proteins that integrate signals from all over the body in order to precisely regulate when, where and how long genes are active. Robert Tjian, of UC Berkeley, presented recent findings from his lab about how embryonic stem cells are regulated by a unique, stem-cell-specific co-activator complex.
A majority of the talks were devoted to how transcriptional regulation, including control by transcription factors, co-activators and epigenetics, delicately balances numerous processes in the body.
For example, Ron Evans, a scientist at the Salk Institute, discussed the regulation of muscle formation and weight maintenance. He showed experiments performed in his lab in which tipping the balance of muscle formation to favor “slow-twitch” muscle fibers leads to mice that can run twice as far as normal mice, and don’t gain weight when fed a high-calorie meal. This research could aid people suffering from type-II diabetes.
Loss of transcriptional balance can lead to several types of diseases. Shigeki Kato from the University of Tokyo and Gerard Karsenty of Columbia University talked about how a disruption in the balance of bone formation and bone resorption can lead to osteoporosis and the approaches that their labs are taking to treat bone disease.
Eric Olsen from the University of Texas Southwestern presented work from his lab about a disruption in transcriptional regulation that leads to heart failure and possible new treatments.
The research described here is just a taste of the wide variety of research described at the Diseases of Transcription Symposium. Taken together, the research presented in San Diego represents the latest advancements in the field of transcription.