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Brain Cell Features Detailed in Human Cell Atlas Research Collection

Brain genetics

NEW YORK – A new collection of studies has provided a look at brain cell composition, function, development, variation, and potential vulnerabilities in human and nonhuman primates.

The diverse research efforts — funded through the National Institutes of Health (NIH) "Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative" — are part of a five-year effort known as the BRAIN Initiative Cell Census Network (BICCN). The resulting data, generated by multiple international research teams, are housed in the Human Cell Atlas.

"Our atlas is already being used by scientists all over the world," Karolinska Institute researcher Sten Linnarsson, the study's senior author, explained in an email.

Still, he called the collection "a first draft human atlas" that will continue to grow as investigators apply the approaches used for the current atlas to samples from larger and more diverse donor individuals and spatially defined brain sites.

In one of a dozen new studies in Science, Linnarsson and colleagues at the Karolinska Institute, the Allen Institute for Brain Science, and the University of Washington used single-cell RNA sequencing on more than 3 million individual cells to come up with gene expression-based clusters representing brain cell types, subtypes, and cell states originating in 100 postmortem forebrain, midbrain, and hindbrain samples from three deceased adult donors.

In the process, the team unearthed some 3,313 gene expression-based sub-clusters falling in 461 broader clusters and 31 "superclusters" for the cells. The cell subsets represented neuron and non-neuron cells, offering a look at cell types, functions, and diversity in the adult human brain. The results revealed overall complexity in the brain, while highlighting the extent of the complexity and cellular diversity that exists in the human brainstem rather than the more widely studied cerebral cortex.

"About two-thirds of the cell types were found outside the cortex," Linnarsson noted, "showing how little we still know about regions outside the cortex."

For another Science study, investigators at the Salk Institute for Biological Studies, University of California, San Diego, and elsewhere used single-nucleus DNA methylation sequencing and single-cell chromatin conformation sequencing to assess DNA methylation marks and 3D DNA features, respectively, in 517,000 brain cells in 46 regions from three adult male donor brains.

"Our work actually went beyond just a survey on brain cell types," co-first author Wei Tian, a researcher with the Salk Institute for Biological Studies Genomic Analysis Laboratory, said in an email. "In particular, we focus on the gene regulatory mechanisms underlying complexity and diversity of brain cell types."

Tian noted that DNA methylation marks unearthed in the collection may prove useful for identifying, studying, or targeting certain brain cell types, for example, potentially providing an avenue for noninvasive disease diagnosis strategies in the future.

A UCSD-led study, also published in Science, offered clues to the DNA methylation underpinnings of neuropsychiatric conditions such as schizophrenia, bipolar disorder, major depressive disorder, and Alzheimer's disease.

For that analysis, investigators turned to single-cell RNA-seq, single-cell DNA methylation profiling, and single-nucleus ATAC-seq-based chromatin accessibility approaches — coupled with machine learning — to profile regulatory features found in more than 1.1 million human brain cells from 42 brain regions in the adult donor brains.

"The collection of orthogonal datasets on the same brain regions in a coordinated manner provided us with an excellent opportunity to investigate the molecular and cellular structure of the human brain," senior and corresponding author Bing Ren, a cellular and molecular medicine researcher at UCSD, explained in an email.

The work revealed 107 brain cell subtypes and a wide range of regulatory elements, he noted, including gene regulatory features that appeared to be preferentially active in certain cell types. Along with efforts to distinguish conserved chromatin features through comparisons to mouse brain data, that arm of the brain atlas effort is expected to help in understanding everything from brain cell-related regulatory clues to regulatory features linked to genetic risk variants implicated in neurological conditions.

Beyond brain cell types, diversity, and regulation, studies in the atlas collection dug into details of human brain development, diversity, disease susceptibility, and more.

For example, Linnarsson and coauthors in Sweden and the UK used single-cell RNA-seq and fluorescence in situ hybridization-based spatial mapping on nearly 1.7 million individual cells from 26 fetal brain samples to follow first trimester brain development between five and 14 weeks after conception, while a University of California, San Francisco-led team performed single-nucleus RNA-seq on more than 700,000 individual cells from 106 pre- and post-natal donors.

For their part, investigators at Icahn School of Medicine at Mount Sinai and Yale University School of Medicine reporting in Science Advances shared a multiomics-based atlas that included gene expression and chromatin accessibility profiles for more than 45,500 nuclei from the human cerebral cortex at half a dozen developmental time points, from early gestation to adulthood — analyses that made it possible to pick out regions that tend to be altered in individuals with bipolar disorder, schizophrenia, or other conditions.

Researchers at the Allen Institute for Brain Science, the Swedish Neuroscience Institute, and the University of Washington performed single-nucleus RNA-seq on samples donated by 75 adult individuals who had tumor surgery or surgery to treat epilepsy, using the data to explore the extent of brain cell variation from one individual to the next.

In Science Translational Medicine, meanwhile, investigators from the University of Maryland School of Medicine, University of Maryland School of Nursing, and Johns Hopkins School of Medicine considered gene expression and chromatin accessibility profiles associated with maturation or inflammation in the developing brain, highlighting transcriptomic shifts in inhibitory neurons known as Purkinje neurons and Golgi neurons.

"Cell-specific patterns of differential gene expression in cerebella of children with inflammation were consistent and suggestive of premature downregulation of developmental gene expression programs," authors of that study wrote, "including a profound decrease in expression of many genes previously implicated by loss-of-function mutations as influencing risk for neurodevelopmental disorders."

Still other studies, published in Science family journals on Thursday, focused on the human neocortex or brain features found in nonhuman primates such as marmosets or rhesus macaques.

In one of the macaque studies, for example, investigators generated nearly 2.6 million single-cell transcriptomes and almost 1.6 million epigenomes in 30 rhesus macaque brain regions, making it possible to predict about 1.2 million suspected regulatory elements.

"Our data, which we have made open and available to the scientific community and broader public, represent the largest and most comprehensive multimodal molecular atlas in a primate to date," Jay Shendure, a genome sciences researcher at the University of Washington, said in a statement, calling the data "crucial for exploring how the many cells of the brain come together to give rise to the behavioral complexity of primates including humans."