The first “multiome” atlas of cellular development in the human cerebral cortex, from birth to adulthood

A team of researchers from the Icahn School of Medicine at Mount Sinai and the Yale University School of Medicine has created the first “multiome” atlas of brain cell development in the human cerebral cortex across six major time points. development, from fetal development to 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 copies of RNA that the cell makes from the genome; and the epigenome, the chemical modifications and regulatory factors that determine chromatin accessibility.

As described in Scientists progress, researchers used new scientific tools to analyze and describe two types of information coming from each cell: gene expression (transcriptome) as well as DNA structure (epigenome), allowing them to categorize the types of cells at different stages of development. The data revealed specific changes in chromatin structure that precede gene expression. These changes are crucial for many processes, including the formation of neurons.

Additionally, their analysis identified chromatin regions associated with the regulation of genes known to play a central role in human brain development. In particular, they revealed that these regulatory regions are often enriched in genetic signals associated with an increased risk of neuropsychiatric disorders such as schizophrenia or bipolar disorder.

“Human brain development begins during embryogenesis and continues after birth through infancy, childhood, adolescence, and early adulthood,” explains Panos Roussos, MD, Ph. .D., professor of psychiatry, genetics and genomic sciences, director of the Center for Neurogenomics of Diseases. at Icahn Mount Sinai and lead author of the article.

“Given the variable age of onset of different neurodevelopmental disorders, it is essential to examine the effect of risk factors across the entire spectrum of brain development. Through the development of this atlas, we have gained a deeper understanding of the complex regulatory mechanisms underlying the brain. development and disease. »

The full atlas is now available to other researchers through an online repository so that others can interact with the data, visualize it effectively, and use it for their own research. The article is part of a set of 21 research studies across Science, Scientists progress And Scientific translational medicine which 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 brains at the cell type level in unprecedented detail .

The causes of neuropsychiatric diseases in adulthood can often be influenced by alterations in the cellular composition of the brain that occur 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 extend beyond existing knowledge by mapping the cell type and temporally specific genetic loci involved in neuropsychiatric disorders. For example, they found 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 these findings 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 must be personalized to target deficiencies in gene function as specific developmental stages,” says Jaroslav Bendl, Ph.D., assistant professor of psychiatry, genetics and genomic sciences at Icahn Mount. Sinai and co-author of the work. “Only in this way can we minimize further harm and improve outcomes for those affected by these disorders.”

Having demonstrated that an atlas of cellular development in the human cerebral cortex was possible, the team is now expanding their study by analyzing a larger cohort of samples and including different regions of the brain. In doing so, they aim to achieve increased resolution, better understand complex regulatory mechanisms, and further unravel the complex regulatory logic underlying brain development and disease.