They undergo transcriptional tryouts leaving cells open to metamorphosis.

Contrary to previous assumptions, human genes do not exist in either an ‘on’ or ‘off’ state, but rather, hover between the two settings, according to researchers at Whitehead Institute for Biomedical Research.

“Surprisingly, about one-third of our genes, including all the regulators of cell identity, fall into this new class,” says Richard Young, an MIT professor of biology. “It seems awfully risky for an adult cell to leave genes primed, when that could change its identity.”

Scientists have known for years that a cell hides the genes it doesn’t need by coiling the dormant DNA tightly around histones. According to the Whitehead study, however, DNA packaging stays loose at the beginning of many inactive genes. The research also suggests that genes begin the process of transcription but fail to finish so that proteins never appear.

Whitehead postdoctoral researchers Matthew Guenther and Stuart Levine screened the entire human genome for a chemical signature—a landmark—that corresponds with this looser DNA packaging configuration and thus with transcription initiation. They worked with embryonic stem cells, liver cells, and white blood cells.

“We expected to find the landmark on 30 to 40 percent of the genes because that’s how many are active in each cell,” Guenther says. “We were shocked when it showed up on more than 75 percent of the genes in both unspecialized embryonic stem cells and specialized adult cells.”

The team went on to confirm that the majority of inactive genes undergo transcriptional tryouts. They begin making RNA but never complete the job. Most of an inactive gene remains tightly coiled around histones, which prevents the RNA transcriptional machinery from progressing along the DNA.

The Whitehead Investigators note that this includes all the genes responsible for directing cells along particular developmental paths, even though they should have no reason for gearing up in healthy specialized cells. Activating such genes might cause a cell to assume new properties.

The team believes such vulnerability to metamorphosis could explain why some cells acquire new, unhealthy states like in cancer or autoimmune diseases. “This is a new model for regulation of the developmental regulators,” Young maintains. “It could bring us a step closer to reprogramming cells in a controlled fashion, which has important applications for regenerative medicine.”

This research, funded by the NIH, appears online in Cell.

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