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Over the past decade, research in the field of epigenetics has revealed that chemically modified bases are abundant components of the human genome and has forced us to abandon the notion we’ve had since high school genetics that DNA consists of only four bases.
Now, researchers at Weill Cornell Medical College have made a discovery that once again forces us to rewrite our textbooks. This time, however, the findings pertain to RNA, which like DNA carries information about our genes and how they are expressed. The researchers have identified a novel base modification in RNA which they say will revolutionize our understanding of gene expression.
Their report, published May 17 in the journal Cell, shows that messenger RNA (mRNA), long thought to be a simple blueprint for protein production, is often chemically modified by addition of a methyl group to one of its bases, adenine. Although mRNA was thought to contain only four nucleobases, their discovery shows that a fifth base, N6-methyladenosine (m6A), pervades the transcriptome. The researchers found that up to 20 percent of human mRNA is routinely methylated. Over 5,000 different mRNA molecules contain m6A, which means that this modification is likely to have widespread effects on how genes are expressed.
While we are all familiar with the role of methyltransferase in DNA and protein modification in the nucleus, (think epigenetics with regards to DNA), this is the first time that methylation in the cytoplasm has been shown to promote protein complex formation.
The researchers first identified an enzyme which is mainly present in the cytoplasm and which methylates the amino acid lysine (Smyd2). Then they searched for interaction partners of the enzyme Smyd2
and found the heat shock protein Hsp90. The scientists went on to show that Smyd2 and methylated Hsp90 form a complex with the muscle protein titin.
According to the authors, “Titin is the largest protein in the human body and known primarily for its role as an elastic spring in muscle cells. Precisely this elastic region of titin is protected by the association with methylated Hsp90.”
In skeletal muscle cells of the zebrafish, the team explored what happens when the protection by the methylated heat shock protein is repressed. By genetic manipulation they altered the organism in such a way that it no longer produced the enzyme Smyd2, which blocked the methylation of Hsp90. Without methylated Hsp90, the elastic titin region was unstable and muscle function strongly impaired; the regular muscle structure was partially disrupted.
Click here for a link to the Genes and Development paper.
Bedtime stories in Dr David Schaffer’s childhood home were often not standard fairy tales. With both parents in careers as biomedical researchers (his mother in drug development and clinical trials for a major pharmaceutical company and his father, in cardiovascular research and a pharmacology professor) much of the conversation as far back as Schaffer can remember centered on biology and science. “I remember being five years old and sitting on my father’s lap, while he was teaching me the names of microorganisms,” says Schaffer. In many ways, a life dedicated to solving biological problems seemed predetermined, but Schaffer did deviate slightly from the examples and influences of his parents and initially concentrated on the engineering aspects of the field.
Schaffer completed his undergraduate work at Stanford University in chemical engineering and graduate work in chemical engineering at MIT. His postdoctoral work was in the laboratory of Dr Fred Gage, a neurobiologist at the Salk Institute for Biological Studies. “For two years, I was the only engineer at the Salk Institute, and had immersed myself in the rich world of biology in a lab that had been making some paradigm-shifting discoveries in the field of neural stem cells and understanding how the adult brain continues to add neurons,” says Schaffer. It was during this pivotal period that Schaffer became fascinated with applying engineering approaches to the study of problems in stem cell biology.
Don’t worry if your brain’s not so stable after all. Neither is mine!
Johns Hopkins scientists investigating chemical modifications across the genomes of adult mice have discovered that DNA modifications in non-dividing brain cells, thought to be inherently stable, instead underwent large-scale dynamic changes as a result of stimulated brain activity. Their report, in the October issue of Nature Neuroscience, has major implications for treating psychiatric diseases, neurodegenerative disorders, and for better understanding learning, memory and mood regulation.
Specifically, the researchers, who include a husband-and-wife team, found evidence of an epigenetic change called demethylation — the loss of a methyl group from specific locations — in the non-dividing brain cells’ DNA, challenging the scientific dogma that even if the DNA in non-dividing adult neurons changes on occasion from methylated to demethylated state, it does so very infrequently.
A recent study published in Science has shown that potential interbreeding between Neanderthals, Denisovans and Modern Humans may have helped boost modern man’s immune system. Many reviews have already been published on this subject (see Science 2.0 for a good review or the ScienceDaily news release) and so we won’t dwell on the subject in this post. However, in light of these findings we would like to share with you a YouTube interview with Svante Pääbo, a Neanderthal researcher, produced by The DNA Learning Center in 2009.
It’s interesting to see how far we’ve come in just 2 short years!
