Mount Sinai researchers probe ‘junk DNA’ for neurological clues
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
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"Many neurological disorders are unique to human and arevery hard as a clinical syndrome to study in animals, such as Alzheimer'sdisease, autism, and depression," says Dr. Schahram Akbarian, a psychiatry andneuroscience professor at the Mount Sinai School of Medicine, and one of theauthors of the study. "By studying epigenetics we can learn more about thoseunique pieces of the human genome."
Akbarian is internationally known for his research on theepigenetic mechanisms of psychiatric disorders, and he is a widely recognizedexpert in advanced chromatin tools—many of which were developed in hislaboratory—in conjunction with mouse mutagenesis and behavioral models ofmental illness to bridge molecular, cellular and behavioral investigations. Heis also a renowned authority on the epigenetic analysis of human brain tissueexamined postmortem.
Seeking to identify the differences between human andprimate genomes, Akbarian and his colleagues tackled the nearly 40 millionpositions in the human genome with DNA sequences that are different than thosein non-human primates—a task that has daunted scientists until now. Theyovercame this hurdle by examining the chromatin, the structure that packagesthe DNA and controls how it is expressed, and discovered that hundreds ofregions throughout the genome showed a markedly different chromatin structurein neurons in the prefrontal cortex compared to those in primates.
"While mapping the human genome has taught us a great dealabout human biology, the emerging field of epigenomics may help us identifypreviously overlooked or discarded sequences that are key to understandingdisease," says Akbarian. "We identified hundreds of loci that representuntapped areas of study that may have therapeutic potential."
The researchers isolated small snippets of chromatin fibersfrom the prefrontal cortex and analyzed them to determine what genetic signalsthey were expressing. Changes observed by the researchers includedspecies-specific regulation of methylation marks on the histone proteins aroundwhich genomic DNA is wrapped. Sequences subject to human-specific epigeneticregulation showed significant spatial clustering, and despite being separatedby hundreds of thousands of base pairs on the linear genome, they were indirect physical contact with each other through chromosomal looping and otherhigher order chromatin features.
Interestingly, any of the sequences with human-specificepigenetic characteristics were, until recently, considered to be "junk DNA"with no particular function (for more on the "junk DNA" issue and recentdevelopments, 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 hasevolved.
"This observation raises the intriguing possibility thatcoordinated epigenetic regulation via newly derived chromatin features at genetranscription start sites could play an important role in the emergence ofhuman-specific gene expression networks in the brain," the team observed.
"There is growing consensus among genome researchers thatmuch of what was previously considered as 'junk sequences' in our genomesindeed could play some sort of regulatory role," says Akbarian.
Finally, the researchers identified a strong geneticfootprint of hominid evolution in a small subset of transcription start sitesdefined by human-specific gains in histone methylation, with particularlystrong enrichment in prefrontal cortex neurons. For example, the base pairsequence of DPP10 (a gene critically important for normal human braindevelopment) not only showed distinct human-specific changes, but also evidencefor more recent selective pressures within the human population.
The prefontal cortex, a brain region that controls complexemotional and cognitive behavior, has been implicated in, personalityexpression, decision-making and moderating social behavior. Thus, the MountSinai study may provide important insights for diseases that are unique tohumans, such as Alzheimer's disease and autism.
Next, Akbarian and his colleagues will execute epigeneticstudies in other areas of the brain to see if there are additional chromatinregions that are unique to humans. They also plan to study the epigenomes ofother mammals with highly evolved social behaviors, such as elephants.
The study was supported by grants from the U.S. National Institutes ofHealth. Other authors on the study were Hennady P. Shulha, Jessica L. Crisci, DenisReshetov, 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.
