All the cells in our body originate from one and all contain the same DNA sequence that encodes the operating instructions for all cell types in the body. Each cell type knows how to activate only the genes it needs to act properly.
Already in the 1980s, in the pioneering work of Hebrew University of Jerusalem (HU) biology Prof. (emeritus) Howard (Chaim) Cedar (who received the Israel Prize, will mark his 80th birthday next week and is still active in research) and the late HU molecular biologist Prof. Aharon Razin, it became clear that this control is achieved by methylation.
This is the chemical marking of the DNA at specific sites using a methyl group (carbon and three hydrogens) – which silences the genes that are not supposed to be in use.
However, the mechanisms responsible for the silencing and activation of genes, including the genomic regions that are essential for the function and identity of each type of cell in the human body, have – until now – not been fully deciphered.
The findings, published today in the prestigious journal Nature under the title “A DNA methylation atlas of normal human cell types,” genomic regions that are responsible for the silencing and activation of genes are identified.
The team of researchers, led by Prof. Tommy Kaplan, Prof. Yuval Dor, Prof. Ben Glaser, Dr. Judith Magenheim and doctoral students Prof. Netanel Loyfer and Ayelet Peretz, included colleagues from the San Francisco-based biotechnology company GRAIL. They shared with the world’s scientific community a novel epigenetic database and reported major advances in our understanding of how different cells in the human body control their unique characteristics and functions.
What the study reveals
The study presents a broader view of the constellations of DNA methylation signatures present in the human body across dozens of cell types, including cells from the immune, blood, respiratory, cardiac, digestive and vascular systems. This vast database will be a valuable resource for the scientific and medical community and will make it possible to answer fundamental questions in biology and promote new approaches to diagnosing diseases.
“In the last four years, we laboriously separated and isolated [and] enriched the populations of dozens of different types of cells from tissue samples we received from surgical colleagues at Hadassah,” said Glaser. “The major cell types from each tissue were isolated and their methylation signature determined, allowing us to identify genomic regions controlling the expression of genes in individual cell types.
“These regions reveal a new dimension of these cell types, and will allow us to focus on the key genomic regions where changes due to deletions or genetic variation might be involved in misregulation of gene expression and disease,” he added.
Kaplan added that they “developed algorithms and computational tools for representing and analyzing huge amounts of sequenced DNA data, and identified thousands of genomic regions that are uniquely methylated in specific cell types in our body. These regions, most of which are characterized here for the first time, allow us to identify and quantify DNA from specific cell types in an unprecedented precision, and will help determine the proportions of each cell type in composite samples. This precision was made possible both by using a large number of genomic regions (biomarkers), and by the fact that we simultaneously map and analyze multiple DNA methylation sites on each DNA molecule we sequence.
One of the most promising applications of this atlas is in diagnosing diseases using a “liquid biopsy,” said Dor. “Most cell types in our body are subject to constant turnover. When these cells die, they release short fragments of DNA into the bloodstream. The methylation atlas we developed makes it possible to examine these cell-free DNA fragments – which still carry the methylation signatures unique to their cell of origin, thus quantitatively inferring which and how many cells have died in the body recently. This information is of great medical importance.”
“Previous efforts by our team and others have shown that by analyzing methylation patterns of DNA fragments circulating in the bloodstream, it is possible to detect excessive cell death, thus identifying damage to the liver, pancreas, heart, respiratory system, and brain, as well as detect the presence of various types of cancer or metastases in distant organs,” Dor continued.
The most promising and challenging application of the technology is screening to diagnose cancer at early stages, as done by Galleri, GRAIL’s multi-cancer early detection test, which analyses methylation patterns to predict the potential site of origin of a detected cancer signal.
The information embodied in the new methylation atlas will make it possible to develop sensitive and specific biomarkers for DNA from all major healthy cell types in the human body and thus will advance the development of liquid biopsies for the purpose of diagnosing additional diseases including Alzheimer’s, fatty liver and more.