The Icahn School of Medicine at Mount Sinai has launched a new research center dedicated to understanding the influence of epigenomics on the nervous system in healthy and pathological conditions. The Center for Neural Epigenome Engineering aims to dramatically expand Mount Sinai’s ability to conduct research in this area, facilitating new discoveries and the development of long-sought-after treatments for a variety of neurological and psychiatric disorders. Areas of expansion include chromatin biochemistry, chemical biology, protein engineering, and single-cell ‘omics’.
“At Mount Sinai, we are dedicated to cracking the epigenomic codes of the nervous system,” said Ian Maze, PhD, research fellow at the Howard Hughes Medical Institute (HHMI); Professor of Neurosciences and Pharmacological Sciences at Icahn Mount Sinai; and head of the new center. “Our hope for the Center for Neural Epigenome Engineering is that it will be a place where Mount Sinai neuroscientists can utilize the latest epigenomic concepts and methods while working side-by-side with multidisciplinary experts in the field of chromatin biology. . We believe this will create an environment that is currently needed to decipher neural epigenomic codes and translate findings into potential treatments for diseases.
Epigenomics describes a set of molecular and chemical processes that moderate the relationship between genes and the environment that produce traits. These processes alter genetic activity and the structure of chromatin, the mixture of proteins and DNA that make up chromosomes, without altering genetic sequences. The processes have been shown to guide the growth and development of cells in newborns, control the activity of cancer and immune cells, and, more recently, play a critical role in neurological and psychiatric disorders.
“The application of epigenomics to neuroscience began about 20 years ago and has revolutionized our ability to master the complex interactions between genes, the brain, and behavior,” said Eric J. Nestler, MD, PhD, director of The Friedman. Brain Institute at Mount Sinai and a pioneer in the field. “The launch of the new center is a landmark moment for the field of neural epigenomics.”
Dr. Maze’s interest in neural epigenomics also began about 20 years ago. He was in college and pissed off the bees. This was all part of a study on how alcohol affects the brain.
“What really struck me at the time was how profoundly alcohol can alter an animal’s behavior, even sometimes long after the alcohol has worn off,” Dr. maze. “In other words, I felt it had to do something more than just a temporary change in brain chemistry. That’s when I had the intuition that we should be looking at genes in the brain for clues.
He then searched for answers in labs across the country, performed hundreds of experiments, became obsessed with the fields of epigenomics and chromatin biology, and published groundbreaking studies of brain function.
For example, from 2019 to 2022, the Maze Lab published a series of seminal scientific papers that redefined the roles that the neurochemicals dopamine and serotonin play in the brain and how these events may contribute to cocaine addiction and addiction. ‘heroin.
Traditionally, these chemicals were known to function, externally, as messengers that relay neural signals from cell to cell. Dr. Maze’s team has shown that dopamine and serotonin can also enter the nuclei of neurons and epigenomically modify long-term gene activity. In two recent papers, the team showed that blocking this new action with dopamine could counteract the effects of cocaine and heroin addiction in rats.
“For neuroscientists, these were completely unexpected and groundbreaking findings,” said Paul Kenny, PhD, chair of the Nash Family Neuroscience Department at Icahn Mount Sinai. “The results revealed a previously unrecognized and entirely novel function of neurotransmitters in the brain and expanded the possibilities of how neurotransmitters alter brain function during the development of addiction.”
The experience Dr. Maze had with these and other discoveries informed many of the goals set for the new research center.
“One of the main challenges of neural epigenomics is that it still remains a relatively unexplored area of research that often requires the development of new methodologies and tools necessary to truly explore and understand the biological impact of these diverse phenomena. D “In our experience, this requires working with a variety of experts, such as chromatin biochemists, chemical biologists and protein engineers. Their unique perspectives often provide the spark for innovation and discovery,” Dr. Maze said “The new center will therefore focus on five key areas. We plan to apply these lessons to the development of each area.”
The five areas are:
- Development of new chemical methodologies for the study of neuronal epigenomic phenomena live
- Expanding Mount Sinai’s High-Throughput Capacity to Simultaneously Study Epigenomic Mechanisms in Diverse Brain Cell Populations
- Using state-of-the-art structural biology and protein engineering strategies to explore the roles that chromatin may play in the nervous system, in both healthy and diseased states
- Development of single-cell “multi-omics” platforms for brain mapping of chromatin states
- Using Well-Designed Real-Time Experiments to Assess the Roles Newly Discovered Epigenetic Phenomena May Have on Neural Circuitry and Behavior
Farrelly, LA; et al; Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3, Nature, 13 Mar 2019, DOI: 10.1038% 2Fs41586-019-1024-7
Lepack, AE; et al; Histone H3 dopaminylation in the ventral tegmental area regulates cocaine finding, Nature, 10 April 2019, DOI: 10.1126/science.aaw8806
Zhao, S.; Chuh KN; Zhang, B.; et al; Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout, PNAS, 9 February 2021, DOI: 10.1073/pnas.2016742118
Fulton, SL; Mitra, S.; et al; Histone H3 dopaminylation in the ventral tegmental area underlies heroin-induced transcriptional and behavioral plasticity in male rats, 29 Jan 2022, DOI: 10.1038/s41386-022-01279-4
About Mount Sinai Health System
Mount Sinai Health System is the largest academic medical system in New York City, encompassing eight hospitals, a leading medical school, and an extensive network of outpatient practices throughout the greater New York area. Mount Sinai advances medicine and health through education and unparalleled translational research and discovery to provide the safest, highest quality, most accessible and equitable care, and the best value of any system health of the country. The health system includes approximately 7,300 primary and specialty care physicians; 13 day surgery centers in joint venture; more than 415 outpatient practices in the five boroughs of New York, Westchester, Long Island and Florida; and over 30 affiliated community health centers. Mount Sinai Hospital is ranked on US News and World Reports “Honor Roll” of America’s Top 20 Hospitals and is #1 in the nation by specialty: #1 in Geriatrics and Top 20 in Cardiology/Cardiac Surgery, Diabetes/Endocrinology, Gastroenterology/Gastrointestinal Surgery, Neurology/Neurosurgery, Orthopedics , pulmonology/ Pulmonary surgery, rehabilitation and urology. New York Eye and Ear Infirmary of Mount Sinai is ranked #12 in ophthalmology. Mount Sinai Kravis Children’s Hospital is listed in US News and World Reports “Best Children’s Hospitals” among the best in the country in four out of 10 pediatric specialties. The Icahn School of Medicine is one of three medical schools that stood out by several indicators: US News and World Reports “Best Medical Schools”, aligned with a US News and World Report “Honor Roll” hospital and #14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks Mount Sinai Hospital #1 in New York and in the top five worldwide, and Mount Sinai Morningside in the top 20 worldwide.
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