Researchers Use Epigenomics to Understand Psychiatric Diseases
Dr. Akbarian says the key to uncovering the roots of psychiatric diseases may lie in the epigenome—the cellular material that sits on top of the genome
For more than two decades, researchers have scoured the tens of thousands of genes that make up the human genome in an attempt to discover what causes disease. Uncovering defects in DNA has furthered our understanding of many ailments, including breast cancer and cystic fibrosis. However, when it comes to uncovering the roots of psychiatric diseases like schizophrenia or bipolar disorder, and understanding brain structure and function, researchers are finding that they need to dig deeper than studying DNA on a linear genome.
Scientists in the Division of Epigenomics at the Icahn School of Medicine at Mount Sinai believe those answers may lie in the cellular material that sits on top of the genome, which is known as the epigenome. This epigenome contains epigenetic marks, which are responsible for gene expression and the myriad of chemical reactions that occur within the human body. It is thought that these epigenetic marks are what allow environmental factors like diet, stress, or toxins to turn genes on or off, and ultimately change the way our bodies act. Led by Schahram Akbarian, MD, PhD, Professor of Psychiatry, the division’s goal is to study these changes in gene activity on the epigenome, which are not involved in our basic genetic code, but still get passed on to the next generation.
“Human biology and the development of disease cannot be deduced by simply sequencing the human genome,” says Dr. Akbarian. “Understanding how the epigenome of neurons and other brain cells are regulated during the course of normal development, and how they may be altered in disease, is the key to developing the next generation of therapies to treat neurological and psychiatric diseases.”
For example, in autism spectrum disorder, very little is known about the biological underpinnings of the disease. As a result, Dr. Akbarian and his team have been studying the disease on the molecular level to try and determine whether or not epigenetic changes may contribute to the development of autism. Recently, his team created the first epigenetic risk map of the prefrontal neurons by examining the post-mortem brain of autism patients. The group created the risk map by developing a novel approach for isolating and characterizing small snippets of chromatin fibers—located in the nucleus of the cell—from neurons in the prefrontal cortex and other brain regions. They then compared those tissues with control subjects and charted for genetic modifications such as DNA and histone methylation markings, which define chromatin structure and function. Their work was published in the Archives of General Psychiatry.
“Neurons from subjects with autism show changes in chromatin structures at hundreds of loci genome-wide, revealing considerable overlap between genetic and epigenetic risk maps of developmental brain disorders,” said Dr. Akbarian in a press release last year. “Our study is the first clear evidence gained exclusively from nerve cells pointing to a link between epigenetic changes and known genetic risk sites for autism.”
In another collaborative project, which involves laboratories based in the United States, Switzerland, and Russia, Dr. Akbarian’s team helped identify hundreds of short DNA sequences defined by epigenetic signatures and chromatin architectures that are unique to human neurons and not shared with any other primate species. “This work is important,” explains Dr. Akbarian, “because neurons, with their intricately complex brain circuitries, are ultimately at the core of our unique cognitive abilities, and potentially our vulnerability to a wide range of ‘human-specific’ diseases from autism to Alzheimer’s.”
The team’s findings, which involve approximately 1,000 base pair long stretches of DNA with human-specific epigenetic signatures, are providing researchers with interesting new leads into the evolution of the human brain. For example, most of these sequences seem to remain constrained since human lineage split from the last common ancestor shared with present-day non-human primates. However, according to Dr. Akbarian, some of these DNA sequences continued to change during subsequent evolution. As a result, some of the DNA defined by histone methylation specific to human neurons contains sequence motifs absent in the genome of other primates. They include two other members of Homo with a sequenced genome: the Neanderthal and the Denisovan.
In other research, the Division of Psychiatric Epigenomics is trying to better understand mood and psychosis spectrum disorders by studying mice. Through genetic engineering and experimental pharmacology, scientists are altering brain chromatin structures and recording the subsequent changes in mice behavior. Dr. Akbarian says this work could help inform therapeutics for debilitating psychiatric disorders such as bipolar disorder and schizophrenia.
“It is an exciting time to be in the field of neuroepigenetics,” he says. “I expect that our approaches will help to uncover novel avenues for the treatment of psychiatric diseases, and help us to understand the similarities and differences in the epigenetic regulation of the genome inside the brain cells of mice, monkeys, and humans.”