UC San Diego, Salk and others try to map the human brain for life

A cross section of the middle temporal gyrus region of a male human brain using spatial transcriptomics, a technique that distinguishes cells based on their genetic data and uses that information to map cells to their original locations.

Credit: Salk Institute

Mapping the human brain

In the new project, researchers will examine 1,500 brain samples (50 regions each in 30 aged human brains). The center will focus not only on the gene expression patterns of each cell, but also on DNA methylation, chromatin organization and histone modifications in the nucleus, molecular events that influence whether genes are turned on or off. In a particular type of cell or at a particular time.

UC Irvine team members will primarily handle the acquisition of brain samples. Salk’s scientists will isolate each nucleus from each individual cell in each region and record molecular details, such as chromatin architecture and DNA methylation. Chromatin architecture allows regulatory elements to communicate with remotely located genes. DNA methylation is the process by which DNA is altered by chemical tags, changing gene expression.

Ren’s team includes Quan Zhu, PhD, and Nathan Zemke, PhD, both associate directors of UC San Diego School of Medicine’s Center for Epigenomics, a collaborative research center specializing in the development and application of leading epigenomic technologies for research. biomedical.

Ren’s team will map histone modifications and gene expression together at single cell resolution. Histone modifications are chemical changes in histone proteins, which make up cell nucleosomes.

“By examining histone modification along with gene expression,” said Ren, “we will be able to chronicle the status of genes and their regulatory elements for tens of millions of cells in the brain and throughout life.”

Ren’s team will also map the spatial distribution of hundreds of millions of brain cells.

“This information will define the structures and cellular composition of different neural circuits in unprecedented detail,” said Ren, “providing a reference for the study of a broad spectrum of neurological diseases.”

Earlier this year, Ren’s team received a $ 10.6 million grant, in collaboration with colleagues at Sanford Burnham Prebys, to create a comprehensive atlas of how and where aging cells accumulate. . The NIH grant is part of the Cellular Senescence Network program.

Currently, such detailed information, particularly regarding the human brain, is scarce, almost non-existent.

“Basically, we want to take millions, even hundreds of millions of brain cells, learn everything we can about their epigenetics and how their chromatin is organized and project them into a spatial context so that we can see where these cells live and understand how. all cells in any region of the brain are organized and at any age, ”Ecker said.

Technology and data

When researchers typically study a single cell, the cell is removed from the rest of the brain, which limits the conclusions that can be drawn. To overcome this, the researchers will use a newer technique called spatial transcriptomics to distinguish cells based on their genetic data and use that information to map cells to their original locations.

Specifically, the team will leverage a technology known as Multiplexed Error Robust RNA FISH (MERFISH) that can detect and quantify the RNA transcripts of hundreds of genes in each cell, while also recording the anatomical location of the cell.

Ren’s lab recently invented a tool, known as the Paired-Tag, which simultaneously maps histone modifications and gene expression from the same cells at very high throughput. The combined maps will enable the generation of integrative maps of histone modifications, gene expression, DNA methylation and chromatin architecture, for cell types in the human brain and throughout life.

Ecker estimates that his lab alone will generate 11 petabytes of raw data during the project, the equivalent of 171,875 USB sticks (64GB each), underscoring the center’s expertise and resources in computational biology, data storage and analysis. Washington University team members will be responsible for data management and integration.

“With the announcement of the BICAN Awards, we are making an exciting transition into the BRAIN Initiative’s overall cell census program, which began in 2014,” said John Ngai, director of the NIH BRAIN Initiative. “These awards will enable researchers to explore the multifaceted characteristics of the more than 200 billion neurons and non-neuronal cells in the human brain in unprecedented detail and size – a feat in advanced technologies and research collaboration between teams that will reveal new paradigms for understanding as pathological changes in particular groups of brain cells could cause neurological and neuropsychiatric disorders ”.

Information on the NIH BRAIN initiative

The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative is a large-scale effort that seeks to deepen understanding of the inner workings of the human mind and improve the way we treat, prevent and cure brain disorders. Since its initial funding in 2014, the BRAIN Initiative has awarded over $ 2.4 billion in research awards. BRAIN Cell Census Network (mouse brain map) and BRAIN Cell Atlas Network (human brain map) are subsets of the BRAIN initiative.

About UC San Diego Health

UC San Diego Health, the region’s only academic healthcare system, is dedicated to providing exceptional patient care through community engagement, groundbreaking research, and inspired teaching. Its specialist care for severe and complex conditions is consistently ranked among the best in the nation by US News & World Report and other organizations. The 808-bed academic healthcare system includes Hillcrest UC San Diego Medical Center and Jacobs Medical Center, Sulpizio Cardiovascular Center, Moores Cancer Center, Shiley Eye Institute, Koman Family Outpatient Pavilion, and Altman Clinical and Translational Research Institute, all in La Jolla, as well as primary care and same-day services at clinics throughout Southern California. For more information, visit health.ucsd.edu.

Information on the Salk Institute for Biological Studies

Every cure has a starting point. The Salk Institute embodies Jonas Salk’s mission to dare to make dreams come true. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology, and more. The Institute is an independent non-profit organization and architectural reference point: small by choice, intimate by nature and fearless in the face of any challenge. Whether it’s cancer or Alzheimer’s, aging or diabetes, Salk is where the treatments begin. Learn more at salk.edu.

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