Highlights •In vivo tracing of parent-specific DNA methylation dynamics at single-cell resolution •Cell-type-specific methylation signatures at the Dlk-Dio3 IG-DMR during development •Dynamic parent- and cell-type-specific DNA methylation changes in the adult brain
Parental imprinting – a form of gene control passed down from parents to offspring – is far more dynamic than previously thought and may contribute to changes in the brain and other tissues over time. This finding by Whitehead Institute scientists challenges current understandings of gene regulation via DNA methylation, from development through adulthood. Methylation – attachment of methyl groups to DNA – is an epigenetic phenomenon that affects gene expression. Generally, methylated genes are turned off while unmethylated genes are active and ready for transcription. Although advances in sequencing technology have yielded informative methylation maps in a variety of tissues, such approaches only capture static “snapshots” of methylation and are unable to reveal the dynamics of methylation in real time in tissues and individual cells.
Because of this limitation, researchers have theorized that inherited methylation largely remains stable throughout development, except during two important developmental milestones: after fertilization and during the creation of sperm and egg cells. Altered gene imprinting at other times has been associated with developmental disorders and cancer. To investigate active methylation in individual cells, Jaenisch lab postdoctoral researcher Yonatan Stelzer developed a reporter system that tracks genomic methylation in real-time. When a target gene is unmethylated, the reporter is also unmethylated, triggering expression of a glowing protein that illuminates the cell. When the target is methylated, so too is the reporter. The glowing protein is then unexpressed, leaving the cell dark. As the target gene’s methylation changes, so does the reporter’s.
In the latest research Stelzer used the reporter system in mice to discover that imprinted methylation in developing and adult tissues is actively regulated rather than merely maintained in stable fashion. “What we see with the reporter in adult tissues is very surprising and much more complex than we had thought,” says Stelzer. “The regulation of imprinted methylation results in these very consistent patterns in different tissues and even in a cell-type dependent manner. In the case of neural cells, it means that imprinted methylation is dynamically shaping the adult brain over time and could play a role in aging. Because this imprinting affects hundreds of genes that are non-coding, including microRNAs and non-coding RNAs, it’s a very interesting fine-tuning mechanism for the dosage of gene expression in the brain and elsewhere in the body.”
Although Stelzer notes that the results of his latest research are indeed exciting, they are just a beginning. “Our work is the first observation of these changes,” he says. “Now we need to understand their functional consequences and the mechanism that regulates these changes in methylation.” http://wi.mit.edu/news/archive/2016/inherited-parental-methylation-shifts-over-time-may-have-functional-effects-brain http://www.pnas.org/content/early/2016/09/07/1605731113.figures-only
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