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UW Medicine researchers at Seattle’s Brotman Baty Institute have created two cell atlases that track gene expression and chromatin accessibility during the development of human cell types and tissues.
An atlas maps gene expression within single cells in 15 fetal tissues. The second atlas maps the chromatin accessibility of individual genes within cells.
Together, the atlases provide a critical resource for understanding gene expression and chromatin accessibility in human development and have an unprecedented scale. The techniques reported in the two articles allow to generate data on gene expression and chromatin accessibility for millions of cells.
The atlases are described in consecutive publications in the November 13 issue of the journal Science. In addition to BBI and UW Medicine, other contributors from Illumina, Inc., University of Arizona, Fred Hutchinson Cancer Research Center, Max Planck Institute for Molecular Genetics, and University of Rochester Medical Center contributed to these studies.
Atlas of gene expression
Gene expression is the process in which a cell uses the instructions stored in its DNA to direct protein synthesis. These proteins, in turn, determine the structure and function of a cell. The Gene Expression Atlas maps where and when gene expression occurs in different cell types as they grow and develop.
“From this data, we can directly generate a catalog of all major cell types in human tissues, including how these cell types might vary in their gene expression in tissues,” said lead author Junyue Cao. PhD. Cao completed this work as a postdoctoral fellow in the lab of Jay Shendure, a professor of genome sciences at the University of Washington School of Medicine, a researcher at the Howard Hughes Medical Institute and scientific director of the Brotman Baty Institute. Cao is now an assistant professor at Rockefeller University.
“There is an overall goal of the field to profile the genetic programs that are present in a human on a larger scale and with the highest possible resolution,” Shendure said.
To create the atlas, the researchers profiled gene expression on 15 types of fetal tissue using a technique called sci-RNA-seq3. This technique labels each cell with a unique combination of three DNA “barcodes”, thus allowing researchers to keep track of cells without physically separating them.
Once the sequences are obtained. Scientists used computer algorithms to retrieve single cell information, group cells by type and subtype, and identify their development trajectories. Scientists profiled over 4 million single cells and identified 77 major cell types and around 650 cell subtypes.
They also compared the atlas to an existing atlas of mouse embryonic development. Senior co-author Cole Trapnell, associate professor of genome sciences at UW School of Medicine and scientist at the Brotman Baty Institute, explained, “When we combine this data with previously published data, we can directly delineate the cell’s development path for all types. “
Atlas of DNA accessibility
The second atlas, DNA accessibility, maps material called chromatin that allows DNA to be securely packed into the cell nucleus. Chromatin can be open and accessible “to the molecular machinery that reads the genetic instructions encoded in DNA or closed and” inaccessible. Knowing the regions of DNA that are open and closed can tell how a cell chooses to turn genes on and off.
“Studying chromatin gives you an insight into the regulatory ‘grammar’ of the cell,” said senior co-author Darren Cusanovich, formerly a postdoctoral fellow in the Shendure lab and now an assistant professor at the University of Arizona. . “The short stretches of DNA that are open, or accessible, are enriched for certain ‘words’, which are, in turn, the basis for which the specific cell wants to turn on certain genes.”
To profile the accessibility of DNA in individual cells, scientists developed a new method, called sci-ATAC-seq3. Like sci-RNA-seq3, this technique also uses three different DNA “barcodes” in each cell to label and track individual cells. However, rather than identifying all currently expressed sequences, sci-ATAC-seq3 acquires and sequences opens the chromatin sites.
In this study, scientists generated nearly 800,000 single-cell chromatin accessibility profiles at approximately 1 million sites in 15 fetal tissues. They asked which proteins could interact with the accessible DNA sites in each cell and how these interactions can explain the cell type. This analysis defines the control switches for development within the genome. They also identified chromatin accessibility sites that could be associated with disease.
“This tells us which part of the genome might be functional. We do not yet know what percentage of the genome that does not code for genes may be involved in gene regulation. Our atlas now provides this information for many cell types, “said Silvia Domcke, co-author of the Atlas paper on accessibility and postdoctoral fellow in the Shendure lab. The other lead authors of the accessibility study. DNA are Andrew Hill, formerly a computational biologist in the Shendure lab and now a scientist at 10x Genomics, and Riza Daza, a researcher in the Shendure lab.
Learn more in Science publications, “A Human Cell Atlas of Fetal Gene Expression” and “A Human Cell Atlas of Chromatin Accessibility”. Explore the data at https://descartes.brotmanbaty.org/
Components of these studies were funded by the Brotman Baty Insitute, the Paul G. Allen Frontiers Foundation, the Chan Zuckerberg Initiative, the Howard Hughes Medical Institute, and the National Institutes of Health.
Press release written by Cognition Studio, Inc. and Michael McCarthy.
Animation created by Dani Bergey and Inessa Stanishevskaya of Cognition Studios, Inc.
NEWS MEDIA RESOURCE: Download the animation
Legend for the scheme
- The cells were obtained from 15 different human organs.
- In the gene expression study, mRNA transcripts were sequenced to identify the expressed genes. In the chromatin accessibility study, open regions of the genome were sequenced to identify which regulatory regions were active. In both cases, the RNA or DNA was “bar-coded” so that their cell of origin could be traced.
- Computer algorithms helped group cells based on their gene expression or their chromatin accessibility profiles.
- Cell type profiles were compared between their organs of origin and with existing databases on gene expression and chromatin accessibility in different developmental stages of mice and humans. This comparison facilitates the use of these atlases in the study of normal and abnormal development and disease.
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