Epigenetics

The human genome is comprised of approximately six billion base pairs (the basic building blocks of genetic coding).  This is a vast amount of genetic information but we are unlikely to gain a deeper understanding of uniquely human brain functions, including cognitive abilities and psychiatric and neurological diseases, merely by studying DNA sequences on a linear genome. This is because less than 1.5 percent of the genome is directly associated with protein encoding genes, and the majority of genetic polymorphisms and DNA variants conferring risk for neurological and psychiatric disease are positioned outside the portions of DNA encoding amino acids. Much of the remaining 98.5 percent of the genome is believed to play an important role in coordinating the regulation of gene expression networks, but gaining deeper insights into these mechanisms has been a challenge.  (Epigenetics is the study of these external or environmental factors that turn genes 'on' and 'off' and affect how cells 'read' genes.) Very little is known about the role of these non-coding and regulatory DNA sequences for normal human brain development, or about their role in changes in the young or old brain, in diseases ranging from autism to Alzheimer's disease. Gaining first insights into these mechanisms is one of the major goals of a world-class team of scientists focused on the neuro-epigenome at Mount Sinai.

Areas of Research

Exploring Epigenetic Drug Targets for the Treatment of Psychiatric Disease

The Friedman Brain Institute is developing novel epigenetic therapies for mood and psychosis spectrum disorders, such as depression and schizophrenia.  This is the major focus of the Division of Psychiatric Epigenomics. Led by Dr. Schahram Akbarian, who directs the Division, researchers are studying novel types of drugs that could alter the chemistry of brain 'nucleosomes' (the cell's chromosomal building blocks, comprised of genomic DNA packaged together with small proteins called histones) in animal models of psychiatric disease. One family of molecules of particular interest are the enzymes that add or remove methyl-groups from lysine and arginine residues of the histone proteins. There are an estimated 100 lysine and arginine residue-specific histone methyltransferase and demethylase enzymes encoded in the human genome, many of which are assumed to play a critical role in maintaining neuronal health and function. These families of molecules are expected to provide plenty of targets for drug discovery and ultimately lead to better treatment options for neurological and psychiatric disease.

Exploring Epigenetic Changes Across the Lifespan of the Human Brain

In addition, the Division of Psychiatric Epigenomics is studying nucleosomal organization and molecular composition in the nuclei of human brain nerve cell specimens collected postmortem in an effort to understand epigenetic changes during the course of normal development and aging across the lifespan, as well as epigenetic changes occurring in chronic psychiatric disease. While it is known that the overwhelming majority of nerve cells in the human brain stop to multiplying via cell division  during prenatal development, extremely little is known about changes inside the nuclei of our nerve cells during the subsequent periods of development, maturation, and aging. It still remains a mystery how the genome in our nerve cells is maintained as we grow up, mature, and age, and how the molecular machinery inside our nerve cells is able to adapt to the myriad environmental influences we are exposed to during our lives. Understanding how epigenetics is important for brain function in healthy brains, as well as those affected by disease is a central research focus of the Division.  

Scientists involved: Schahram Akbarian, Emily Bernstein, Patrizia Casaccia, Fatemah Haghighi, Yasmin Hurd, Paul Kenny, Javier Gonzalez-Maeso, Eric J. Nestler, Scott J. Russo, Anne Schaefer, Li Shen