If you want to declare your identity to the world, you might buy a Prius, grow one of those rat’s-nest hipster beards, or get a tattoo of Justin Bieber. Cells, of course, rely on different ways to establish who they are and what they do. Now, researchers say they’ve discovered a novel mechanism that marks the identities of different kinds of cells in the human body—and prevents them from transforming into another type altogether.
Scientists learned decades ago to read the basic genetic code by which cells convert a string of DNA bases into a protein’s amino acids. But for more than 10 years, they’ve been trying to crack what’s known as the histone code, a more complex cipher embedded within organisms’ genomes. Histones are the proteins that DNA coils around in chromosomes. Chemically tweaking histones in a variety of ways can adjust the activity of genes, turning them up or down. For example, cells shut off genes by attaching three methyl groups to a specific spot on a histone type known as H3. But affixing three methyl groups to another H3 location, a modification known as H3K4me3, has a different effect. Cells typically add the H3K4me3 tags to histones in small sections of the genome, but researchers noticed that sometimes the tag can sprawl across much larger areas, modifying broad swaths of histones.
To find out whether these large blocks of histones carrying H3K4me3 tags convey a message in the histone code, molecular geneticist Anne Brunet of Stanford University in Palo Alto, California, and colleagues traced their occurrence in more than 20 different cell types. They found that the longest stretches pinpoint different sets of genes in different types of cells. As a result, the researchers realized they could discriminate liver cells from, say, muscle cells or kidney cells based only on the chromosomal locations of the largest H3K4me3 blocks. In addition, they noticed that these stretches tended to mark genes that are crucial for a cell type’s function or that help make it distinct. In embryonic stem cells, for instance, they occur on genes that control the cells’ capacity to specialize.
The researchers further demonstrated that the labels mark cell identity genes by using a technique called RNA interference (RNAi) in adult neural progenitor cells, which can morph into any cell type in the brain. As the researchers revealed online today in Cell, they applied RNAi to dial down the genes that carried large blocks of H3K4me3 tags and found that it impaired the cells’ ability to reproduce and to spawn neurons. However, the progenitor cells could still divide normally if the researchers quieted genes that had only short sections of H3K4me3 tags or none at all. In other words, the presence of long stretches of H3K4me3 markers might help cells keep their identities for life. Although cells have several methods for establishing who they are, “we’ve discovered a new signature,” Brunet says.
Epigenomicist Peter Scacheri of Case Western Reserve University in Cleveland, Ohio, is impressed by the paper. “I think it will rock the [research] community,” he says. Although many other scientists have studied H3K4me3 tags, “the concept that this one mark can distinguish all these cell types—that’s a real shocker,” he says. Measuring the tags is easy, he notes, so the discovery could allow quick identification of cell types, which would be useful in situations such as cancer diagnosis.