UCLA scientists receive $10 million to shed light on the development of the brain’s cellular infrastructure

Two scientists at the University of California’s David Geffen School of Medicine have received nearly $10 million from the National Institutes of Health Brain research through the development of innovative neurotechnologies® (BRAIN) is an initiative for research projects aimed at shedding light on the development of the cellular infrastructure of the brain to better understand brain disorders.

Chongyuan Luo, assistant professor of human genetics, has been awarded a grant totaling approximately $5.3 million over five years to systematically map the regulatory landscape of genes across human brain development at a single-cell resolution for the first time. Aparna Bhaduri, assistant professor of biological chemistry, will receive about $4.3 million over five years through a UCSF-led project examining genetic activity and structure across stages of evolution and across species.

The NIH grants were provided through the agency’s Brain Initiative Cell Atlas Network (BICAN), a large-scale effort to comprehensively catalog cell types and molecular characteristics in the brain.

Lo grant: Scientists have hypothesized that many psychiatric disorders result from poor brain development, which is supported by observations that genetic variants associated with a variety of neuropsychiatric disorders are enriched in gene regions that are active during brain development. However, the causal brain structure or cell type of mental disorders is often unknown, making it difficult to develop treatments for mental disorders.

By using two state-of-the-art single-cell technologies, Luo’s research team will map genes’ regulatory regions to understand how associated genetic variants affect brain development. The first, sn-m3C-seq (PMID: 31501549), simultaneously highlights DNA methylation and 3D chromatin structure in the same cell. The second, snmCT-seq (PMID: 35419551), jointly highlights DNA methylation and gene expression from the same cell. The research team will also use the droplet-based single-cell chromatin accessibility assay developed by 10x Genomics to characterize the genes’ regulatory regions.

This effort will allow researchers to build a comprehensive catalog of cell types in the developing brain and to identify regions of gene regulation at a specific cell-type level for hundreds of brain cell types.

The database will greatly improve our study of genetic variants associated with mental and neurological disorders. More specifically, the data set can lead to the discovery of specific cell types and genomic regions that mediate brain disease risk.”

Chongyuan Luo, Assistant Professor of Human Genetics

Luo’s team will collaborate with research groups led by Jason Ernst at UCLA, Mercedes Paredes, Tomasz Nowakowski at UCSF, and Eran Mukamel at UCSD. The grant number for Project Luo is U01MH130995-01.

Bahaduri Scholarship: Her project is part of a $36.4 million grant at UCSF to examine brain development in humans, macaques, and monkeys during 4 stages of development: the peak of prenatal neurogenesis, immediately after birth, infancy, and adolescence. The project aims to determine the types of cells found in the brain of human and nonhuman primates, how they change over time, and how they are spatially organized. Comparing the types will help researchers understand which types of brain cells may be more distinct in humans and therefore may be more susceptible to disease.

“With these answers, we can better understand how the brain develops normally and how it is affected by neurodevelopment and neuropsychiatric disorders,” Bhaduri said.

Bahaduri compared efforts to generate a “parts list” of the developing human brain using a relatively new technique that allows researchers to effectively construct a detailed map. The researchers will use single-celled RNA sequencing to study the genes that are turned on by individual cells, and at the same time they will use single-celled ATAC sequencing to look at the structure of the genome. This will help create important clues to cell types through evolution, and in parallel scans the researchers will examine cells across the spatial landscape on the brain.

The project builds on previous work by Bahaduri and colleagues studying the development of the human cerebral cortex, which enables complex cognition and many other brain structures in early development.

The scholarship includes researchers at multiple institutions, including: Arnold Kriegstein, Tomasz Nowakowski, and Alex Pollen of UCSF; Nenad Sestan and Rong Fan of Yale University; Huang Hao of the University of Pennsylvania; John Levine and Andre Souza of the University of Wisconsin-Madison; and Marcel Daddy of the Texas Biomedical Research Institute. The scholarship number is 1UM1MH130991-01.

“With the announcement of the BICAN Awards, we are making an exciting shift in the BRAIN Initiative’s comprehensive cell census program, which began in 2014,” said Dr. John Ngai, Director of the NIH BRAIN Initiative. “These awards will enable researchers to explore the multifaceted properties of the more than 200 billion neurons and non-neuronal cells in the human brain in unprecedented detail and scale—a breakthrough in advanced technologies and research collaborations between teams that will uncover new models for understanding how pathological changes in specific groups of Brain cells can cause neurological and neuropsychiatric disorders.”

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