Salk Institute researchers, as part of a larger collaboration with research teams around the world, analyzed more than half a million brain cells from three human brains to assemble an atlas of hundreds of cell types that make up a human brain in unprecedented detail.
The research, published in a special issue of the journal Science [1] on 13 October 2023, is the first time that techniques to identify brain cell subtypes originally developed and applied in mice have been applied to human brains.
“These papers represent the first tests of whether these approaches can work in human brain samples, and we were excited at just how well they translated,” says Professor Joseph Ecker, director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator. “This is really the beginning of a new era in brain science, where we will be able to better understand how brains develop, age, and are affected by disease.”
The new work is part of the United States’ National Institute of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative, or The BRAIN Initiative, an effort launched in 2014 to describe the full plethora of cells – as characterized by many different techniques – in mammalian brains. Salk is one of three institutions awarded grants to act as central players in generating data for the NIH BRAIN Initiative Cell Census Network, BICCN.
Every cell in a human brain contains the same sequence of DNA, but in different cell types different genes are copied onto strands of RNA for use as protein blueprints. This ultimate variation in which proteins are found in which cells – and at what levels – allows the vast diversity in types of brain cells and the complexity of the brain. Knowing which cells rely on which DNA sequences to function is critical not only to understanding how the brain works, but also how mutations in DNA can cause brain disorders and, relatedly, how to treat those disorders.
“Once we scale up our techniques to a large number of brains, we can start to tackle questions that we haven’t been able to in the past,” says Margarita Behrens, a research professor in Salk’s Computational Neurobiology Laboratory and a co-principal investigator of the new work.
In 2020, Ecker and Behrens led the Salk team that profiled 161 types of cells in the mouse brain, based on methyl chemical markers along DNA that specify when genes are turned on or off. This kind of DNA regulation, called methylation, is one level of cellular identity.
In the new paper, the researchers used the same tools to determine the methylation patterns of DNA in more than 500,000 brain cells from 46 regions in the brains of three healthy adult male organ donors. While mouse brains are largely the same from animal to animal, and contain about 80 million neurons, human brains vary much more and contain about 80 billion neurons.
“It’s a big jump from mice to humans and also introduces some technical challenges that we had to overcome,” says Behrens. “But we were able to adapt things that we had figured out in mice and still get very high-quality results with human brains.”
At the same time, the researchers also used a second technique, which analyzed the three-dimensional structure of DNA molecules in each cell to get additional information about what DNA sequences are being actively used. Areas of DNA that are exposed are more likely to be accessed by cells than stretches of DNA that are tightly folded up.
“This is the first time we’ve looked at these dynamic genome structures at a whole new level of cell type granularity in the brain, and how those structures may regulate which genes are active in which cell types,” says Jingtian Zhou, co-first author of the new paper and a postdoctoral researcher in Ecker’s lab.
Reference:
- Wei Tian, Jingtian Zhou, Anna Bartlett, et. al. Single-cell DNA methylation and 3D genome architecture in the human brain. Science, 2023; 382 (6667)
doi: https://doi.org/10.1126/science.adf5357
