Ученые создали первую атласную карту эпигенетических систем человека на основе данных 87 тысяч клеток

LA JOLLA – In the nearly 400 years since the initial discovery of the cell, researchers have sought to understand how cells differentiate themselves in tissues throughout the body. Cells like neurons, heart muscle cells, blood cells and skin cells all use the same three billion base pairs of DNA that are in the human genome, but receive directions about how to function and which traits to express via molecular markers that activate or deactivate specific genes. Epigenetics, the study of the mechanisms that cause gene expression to change without alterations to the DNA sequence, provides researchers a window into how cells get their identities and how gene expression is regulated. “We have a massive diversity of cell types in our body, and we regulate them with sequence elements that can turn genes on or off in particular cell types or lineages,” said Dr. Jesse Dixon, an associate professor at the Salk Institute for Biological Studies. “One of the weird things that we’ve done in evolution is we’ve actually moved them further and further away from the genes that they regulate.” Dixon and Salk Institute professor Joseph Ecker – also the Salk International Council chair in genetics and an investigator with the Howard Hughes Medical Institute – were co-corresponding authors on a study published in the journal Science in July establishing the first single-cell atlas of two major epigenetic systems, spanning nearly 87,000 cells from 16 human tissues. Dixon and Ecker partnered with other researchers from Salk, the Bay Area-based Arc Institute, UC San Diego and a number of other universities to measure how seemingly disparate portions of DNA come into contact with each other in three-dimensional space and the effects of DNA methylation, a process by which minute chemical units called methyl groups attach to specific DNA bases that functions as something of a cellular barcode. New Information on Genome The two researchers have been collaborating for seven or eight years, by Dixon’s estimation. Dixon’s lab has historically focused on 3D genomic folding, while Decker’s lab has focused on patterns of DNA methylation. “We’ve been working on this idea of trying to apply this much more comprehensively across the human body, and all the different ways in which our genomes are organized in 3D space across all the different cells of the human body,” Dixon said. The atlas includes data for 35 major cell types and more than 200 subtypes and demonstrates the overlap between a cell’s epigenetic features and genetic risk factors for conditions like atrial fibrillation, bipolar disorder and schizophrenia. The researchers ultimately identified more than 1.3 million differently methylated regions and nearly 300,000 chromatin loops – regions of DNA that are close in physical proximity even if they are in disparate parts of the linear DNA sequence – across the cell types in the study, providing new information about the roughly 98% of the genome that doesn’t encode for proteins. Many genetic variations that are linked to the development of disease occur in the non-coding regions of the genome. That presents a physical challenge for genetic researchers, as the intricate loops and folds of DNA strands can bring regulatory sections of the sequence into contact with a regulated gene that may be more than a million base pairs away, Dixon said. “The DNA methylation aspect is very good at identifying where there are specific regulatory elements in the genome, and we think that with the combined 3D genome aspect of the data, this is actually a really great way to then begin to link those distal elements in this really comprehensive setting to the gene that they potentially regulate throughout the genome,” he said. The study also found that DNA methylation and 3D genome architecture don’t always align in the information they provide about a cell’s identity. In one instance, the researchers found fibers that appeared to be mature muscle cells from their 3D genome folding, but carried the methylation signature of muscle stem cells. “The inconsistency between modalities may be further used to determine what cell populations are switching between each other in adult tissues and diseases, which could, for example, expand our understanding of cancer cell dynamics,” stated Jiantian Zhou, a co-first and co-corresponding author of the study and a researcher at the Arc Institute. The team behind the study built an interactive website to enable researchers to explore the atlas’ DNA methylation and 3D structure data and potentially use it for follow-up experiments. Already Producing Results for Researchers In the same issue of Science that included the atlas study, co-author Bing Ren, a genetics and biochemistry professor at Columbia University and the scientific director and CEO of the New York Genome Center, led and published a study of microglia, the brain’s and spinal cord’s immune cells. Using the atlas’ DNA methylation data, Ren’s study found that microglia are replaced by cells that are similar to white blood cells in patients roughly between the ages of 50 and 75. “You’re going from microglia that arise in the brain that are prenatally established to ones that are basically replaced over time with cells from your bone marrow,” Dixon said. “That’s really wild because the dogma was that you’re born with this particular (portion) of microglia that are derived from embryonic tissue called the yolk sac, and that they basically stay that way for the rest of your life. “I think the study actually really changes the understanding of what’s happening with these cells as people age,” Dixon added. Building on Human Genome Project The atlas study was published as part of a spiritual successor research initiative to the Human Genome Project called the 4D Nucleome project, founded and supported by the National Institutes of Health. The goal of the 4D Nucleome project, according to the NIH, is to determine how the human genome is organized in both space and time as it modulates gene expression in both health individuals and those with serious diseases. The cells collected as part of the atlas study were all from healthy individuals, Dixon said, but the data could be meaningfully different coming from patients of different diseases and among different age cohorts. Eventually, the atlas’ data could be useful in contexts like determining how different mutations in a cancer biopsy relate to each other and demonstrate how a patient’s cancer is evolving over time. “One of the hopes for this would be that it allows you to understand that potential disease type better,” Dixon said. “And maybe in the long run, that actually gives insights in terms of what would be drug targets or pathways to focus on in the future.” Salk Institute for Biological Studies FOUNDED: 1960 PRESIDENT: Gerald Joyce HEADQUARTERS: La Jolla BUSINESS: Scientific research institute WEBSITE: salk.edu(opens in new tab) CONTACT: [email protected] NOTABLE: The Salk Institute was founded by Jonas Salk, the developer of the polio vaccine. Eli is an award-winning reporter primarily covering the tech and life sciences industries. He previously worked as the San Diego City Hall reporter for the regional wire City News Service. He has also covered public health, transportation and state and local politics in the San Francisco Bay Area for Local News Matters, the nonprofit arm of the regional wire Bay City News Service, where he also oversaw the development and daily content management of the outlet’s public health and COVID-19 news and resource webpage. He is also a contributing writer covering Minor League Baseball for the analysis and commentary website Baseball Prospectus. Eli is a graduate of San Francisco State University and a native of Northern California.