A biological process known as genomic imprinting helps control early mammalian development by turning genes on and off as the embryo and placenta grow. Errors in genomic imprinting can cause severe disorders and profound developmental defects that lead to lifelong health problems, yet the mechanisms behind these critical gene-regulating processes — and the glitches that cause them to go awry — have not been well understood.
Now, scientists at Harvard Medical School (HMS) and Boston Children’s Hospital have identified a mechanism that regulates the imprinting of multiple genes, including some of those critical to placental growth during early embryonic development in mice. The results were reported yesterday in Nature.
“A gene that is turned off by epigenetic modifications can be turned on much more easily than a gene that is mutated or missing can be fixed,” said Yi Zhang, PhD, a senior investigator in the Boston Children’s Program in Molecular and Cellular Medicine, a professor of pediatrics at HMS and a Howard Hughes Medical Institute investigator. “Our discovery sheds new light on a fundamental biological mechanism and can lay the groundwork for therapeutic advances.”
Toward a new understanding of genomic imprinting
Genomic imprinting is an epigenetic process that contributes to embryonic development by silencing the gene from one parent — effectively turning the gene off — in the offspring. As a result, only the other parent’s gene is expressed. Sometimes, the process goes haywire and the wrong genes are silenced or expressed by mistake, resulting in growth disorders, developmental delays, learning disabilities, infertility and balance and movement problems. In extreme cases, turning off the wrong genes can prove fatal for the developing fetus.
Nearly 25 years ago, researchers identified DNA methylation — a process cells use to switch genes off by attaching chemicals called methyl groups to parts of their DNA — as the regulating mechanism that drives this critical biological process of silencing one of two parental genes.
“Since its discovery over two decades ago, DNA methylation has been the only known mechanism governing genomic imprinting,” said Asuza Inoue, PhD, a postdoctoral research fellow in Zhang’s lab in the Department of Genetics at Harvard Medical School and the first author of the new paper.
But Zhang’s team was mapping imprinted genomic regions in early-stage mouse embryos, when they noticed mysterious DNA methylation-independent imprinted regions.
“Much to our surprise, the imprinted genes we looked at lacked DNA methylation, which told us there must be another mechanism at play,” Inoue said.
A boon for epigenetic therapies?
Zhang’s team dug deeper into the genomic regions and discovered the consistent presence of H3K27me3, a chemical modification to the genes’ histones, proteins that form the spool around which the thread of DNA is wound.
This histone modification had previously been identified as an epigenetic gene silencing mechanism in other scenarios, but not as a regulator of imprinting, the researchers say. They demonstrated that not only was the histone modification necessary for imprinting certain genes, but that DNA methylation played no role in imprinting them. In a series of experiments, the researchers demonstrated that removing the histone modifier from developing embryos led to the loss of imprinting, which caused expression of both parental genes. At the same time, genes regulated by DNA methylation remained imprinted.
In other words, the researchers said, the DNA methylation-independent imprinted genes identified by researchers in the recent past were, in fact, regulated by H3K27me3. In all, the researchers identified 76 genes potentially imprinted by histone modification rather than by DNA methylation. This set of imprinted genes includes several linked to placental development, limb abnormalities and a disorder associated with severe eye anomalies.
The findings could lead to development of epigenetic therapies for a range of devastating developmental disorders, Zhang’s team said.
In addition to Zhang and Inoue, co-authors on the study are Lan Jiang, Falong Lu and Tsukasa Suzuki.
This work was supported by the Howard Hughes Medical Institute and the Charles A. King Trust Postdoctoral Research Fellowship.
Greta Friar is a science writer at Harvard Medical School. This post was adapted from a press release issued by HMS.