Epigenetic memory consists of patterns of gene expression and repression that are passed from generation to generation, and from cell to cell during development. How epigenetic memory is acquired, preserved, and selectively modified from tissue to tissue remains something of a mystery. Yet details are emerging. One detail, recently uncovered by researchers at UC Santa Cruz, concerns a particular kind of epigenetic modification—the methylation of a DNA packaging protein called histone H3.
Methylation of a particular amino acid (lysine 27) in histone H3 is known to turn off or “repress” genes, and this epigenetic mark is found in all multicellular animals, from humans to the tiny roundworm Caenorhabditis elegans that was used in a UC Santa Cruz study described September 19 in Science, in an article entitled, “H3K27me and PRC2 transmit a memory of repression across generations and during development.”
The article describes how the laboratory led by Susan Strome, Ph.D., a professor of molecular, cell, and developmental biology, created worms with a mutation that knocks out the enzyme responsible for making the methylation mark, then bred them with normal worms. Using fluorescent labels, they were able to track the fates of marked and unmarked chromosomes under the microscope, from egg cells and sperm to the dividing cells of embryos after fertilization. Embryos from mutant egg cells fertilized by normal sperm had six methylated chromosomes (from the sperm) and six unmarked or “naked” chromosomes (from the egg).
As embryos develop, the cells replicate their chromosomes and divide. The researchers found that when a marked chromosome replicates, the two daughter chromosomes are both marked. But without the enzyme needed for histone methylation, the marks become progressively diluted with each cell division.
“The mark stays on the chromosomes derived from the initial chromosome that had the mark, but there's not enough mark for both daughter chromosomes to be fully loaded,” Dr. Strome said. “So the mark is bright in a one-cell embryo, less bright after the cell divides, dimmer still in a four-cell embryo, and by about 24 to 48 cells we can't see it anymore.”
The researchers then did the converse experiment, fertilizing normal egg cells with mutant sperm. The methylation enzyme (called PRC2) is normally present in egg cells but not in sperm, which don't contribute much more than their chromosomes to the embryo. So the embryos in the new experiment still had six naked chromosomes (this time from the sperm) and six marked chromosomes, but now they also had the enzyme.
“Our studies suggest that PRC2 represses the X chromosomes in C. elegans germ cells, and this repression is transmitted to embryos by both sperm and oocytes,” wrote the authors of the Science article. “[Our] results demonstrate that H3K27me and PRC2 each contribute to epigenetically transmitting the memory of repression across generations and during development.”
Dr. Strome noted that the findings in this study of transmission of histone methylation in C. elegans have important implications in other organisms, even though different organisms use the repressive marker that was studied to regulate different genes during different aspects of development. All animals use the same enzyme to create the same methylation mark as a signal for gene repression, and her colleagues who study epigenetics in mice and humans are excited about the new findings, Dr. Strome said.
“Transgenerational epigenetic inheritance is not a solved field—it’s very much in flux,” she explained. “There are dozens of potential epigenetic markers. In studies that document parent-to-child epigenetic inheritance, it's not clear what's being passed on, and understanding it molecularly is very complicated. We have a specific example of epigenetic memory that is passed on, and we can see it in the microscope. It’s one piece of the puzzle.”