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Mount Sinai researchers probe ‘junk DNA’ for neurological clues
NEW YORK—Cognitive abilities and psychiatric diseases unique to humans could be based on genomic features distinguishing our brain cells, including neurons, from those of other primates, according to a new study by researchers from the departments of Psychiatry and Neuroscience at the Mount Sinai School of Medicine. Short strands of DNA found in human brain tissue may provide new insights into human cognitive function and risk for developing certain neurological diseases, posits the study, "Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons," which was published Nov. 20 in PLoS Biology.
"Many neurological disorders are unique to human and are very hard as a clinical syndrome to study in animals, such as Alzheimer's disease, autism, and depression," says Dr. Schahram Akbarian, a psychiatry and neuroscience professor at the Mount Sinai School of Medicine, and one of the authors of the study. "By studying epigenetics we can learn more about those unique pieces of the human genome."
Akbarian is internationally known for his research on the epigenetic mechanisms of psychiatric disorders, and he is a widely recognized expert in advanced chromatin tools—many of which were developed in his laboratory—in conjunction with mouse mutagenesis and behavioral models of mental illness to bridge molecular, cellular and behavioral investigations. He is also a renowned authority on the epigenetic analysis of human brain tissue examined postmortem.
Seeking to identify the differences between human and primate genomes, Akbarian and his colleagues tackled the nearly 40 million positions in the human genome with DNA sequences that are different than those in non-human primates—a task that has daunted scientists until now. They overcame this hurdle by examining the chromatin, the structure that packages the DNA and controls how it is expressed, and discovered that hundreds of regions throughout the genome showed a markedly different chromatin structure in neurons in the prefrontal cortex compared to those in primates.
"While mapping the human genome has taught us a great deal about human biology, the emerging field of epigenomics may help us identify previously overlooked or discarded sequences that are key to understanding disease," says Akbarian. "We identified hundreds of loci that represent untapped areas of study that may have therapeutic potential."
The researchers isolated small snippets of chromatin fibers from the prefrontal cortex and analyzed them to determine what genetic signals they were expressing. Changes observed by the researchers included species-specific regulation of methylation marks on the histone proteins around which genomic DNA is wrapped. Sequences subject to human-specific epigenetic regulation showed significant spatial clustering, and despite being separated by hundreds of thousands of base pairs on the linear genome, they were in direct physical contact with each other through chromosomal looping and other higher order chromatin features.
Interestingly, any of the sequences with human-specific epigenetic characteristics were, until recently, considered to be "junk DNA" with no particular function (for more on the "junk DNA" issue and recent developments, read "Treasure in the junk" from our October issue http://www.drugdiscoverynews.com/index.php?newsarticle=6618), but they are now considered to be important leads on how the human brain has evolved.
"This observation raises the intriguing possibility that coordinated epigenetic regulation via newly derived chromatin features at gene transcription start sites could play an important role in the emergence of human- specific gene expression networks in the brain," the team observed.
"There is growing consensus among genome researchers that much of what was previously considered as 'junk sequences' in our genomes indeed could play some sort of regulatory role," says Akbarian.
Finally, the researchers identified a strong genetic footprint of hominid evolution in a small subset of transcription start sites defined by human-specific gains in histone methylation, with particularly strong enrichment in prefrontal cortex neurons. For example, the base pair sequence of DPP10 (a gene critically important for normal human brain development) not only showed distinct human-specific changes, but also evidence for more recent selective pressures within the human population.
The prefontal cortex, a brain region that controls complex emotional and cognitive behavior, has been implicated in, personality expression, decision-making and moderating social behavior. Thus, the Mount Sinai study may provide important insights for diseases that are unique to humans, such as Alzheimer's disease and autism.
Next, Akbarian and his colleagues will execute epigenetic studies in other areas of the brain to see if there are additional chromatin regions that are unique to humans. They also plan to study the epigenomes of other mammals with highly evolved social behaviors, such as elephants.
The study was supported by grants from the U.S. National Institutes of Health. Other authors on the study were Hennady P. Shulha, Jessica L. Crisci, Denis Reshetov, Jogender S. Tushir, Iris Cheung, Rahul Bharadwaj, Hsin-Jung Chou, Isaac B. Houston, Cyril J. Peter, Amanda C. Mitchell, Wei-Dong Yao, Richard H. Myers, Jiang-fan Chen, Todd M. Preuss, Evgeny I. Rogaev, Jeffrey D. Jensen, Zhiping Weng and Schahram Akbarian.