(Press-News.org) A team of researchers from the Icahn School of Medicine at Mount Sinai and Yale University School of Medicine has created the first “multiome” atlas of brain cell development in the human cerebral cortex across six broad developmental time points from fetal development into adulthood, shedding new light on their roles during brain development and disease.
“Multiome” refers to the simultaneous analysis of multiple types of genetic information within the same biological sample. They can include the genome, the DNA encoded in our cells; the transcriptome, the RNA copies that the cell makes from the genome; and the epigenome, chemical modifications and regulatory factors that determine the accessibility of chromatin,
As described in Science Advances, the researchers used new scientific tools to analyze and describe two kinds of information from each cell—gene expression (transcriptome) as well as DNA structure (epigenome)—enabling them to categorize cell types at different developmental stages. The data revealed specific changes in the structure of chromatin that precede gene expression. These changes are crucial for numerous processes, including the formation of neurons.
Additionally, their analysis pinpointed regions of chromatin associated with the regulation of genes known to play a pivotal role in human brain development. Notably, they revealed that these regulatory regions are often enriched for genetic signals associated with increased risk for neuropsychiatric disorders such as schizophrenia or bipolar disorder.
“Human brain development starts during embryogenesis and extends postnatally through infancy, childhood, adolescence, and young adulthood,” says Panos Roussos, M.D., Ph.D., Professor of Psychiatry, and Genetics and Genomic Sciences, Director of the Center for Disease Neurogenomics at Icahn Mount Sinai, and senior author of the paper. “Given the variable age of onset of different neurodevelopmental disorders, it is critical to examine the effect of risk factors across the full spectrum of brain development. Through the development of this atlas, we have gained a deeper understanding of the intricate regulatory mechanisms underlying brain development and disease.”
This work was supported by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative (The BRAIN Initiative®). The comprehensive atlas is now accessible to other researchers through an online repository so others can engage with the data, visualize it effectively, and use it for their own research. The paper is included in a package of 21 research studies across Science, Science Advances and Science Translational Medicine that detail research conducted as part of the National Institutes of Health’s BRAIN Initiative Cell Census Network (BICCN), a program launched in 2017 to create an atlas of the human and non-human primate brain at the cell-type level in unprecedented detail.
The basis for neuropsychiatric disease in adulthood can often be influenced by alterations in the cellular composition of the brain that arise during development. In addition to creating the first atlas of human brain cell development in the human cerebral cortex, the research team prioritized 152 risk genes that play a causal role in a range of neuropsychiatric disorders. Their findings go beyond existing knowledge by mapping cell type and temporally specific genetic loci implicated in neuropsychiatric disorders. For example, they discovered that Tourette syndrome is associated with oligodendrocytes, while obsessive-compulsive disorder is associated with astrocytes. Both of these associations between diseases and cell types were previously unknown, and the discoveries contribute to a deeper understanding of the complex relationships between different cell types and neuropsychiatric disorders.
“It is important to recognize that the most effective therapeutic interventions should be customized to target deficiencies in gene function as specific developmental stages,” says Jaroslav Bendl, Ph.D., Assistant Professor of Psychiatry, and Genetics and Genomic Sciences, at Icahn Mount Sinai and a co-author of the work. “Only by doing so will we be able to minimize further damage and improve outcomes for individuals affected by these disorders.”
Having demonstrated that an atlas of cellular development in the human cerebral cortex was possible, the team is currently expanding their study by analyzing a larger sample cohort and including different brain regions. By so doing, they aim to achieve increased resolution and gain deeper understanding of the intricate regulatory mechanisms and further unravel the complex regulatory logic underling brain development and disease.
Research reported in this press release was supported by the NIH BRAIN Initiative under award number: RF1MH128970. This publication was supported by and coordinated through the BICCN (biccn.org). This publication is part of the Human Cell Atlas (www.humancellatlas.org/publications/).
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, more than 400 outpatient practices, more than 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,400 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report's® “Best Hospitals” Honor Roll for 2023-2024.
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