Lahn’s group developed a powerful new technique called Potency-Seq, designed to measure a gene’s transcriptional potency – whether a silent gene still has the potential to turn on, or whether it has permanently lost that ability.

Using this approach, the researchers found that as cells specialize, they steadily lose genetic flexibility. Large sections of the genome become permanently locked – a process that Lahn calls “gene occlusion” – and the affected genes can no longer be expressed, even if factors that would normally activate these genes are present in cells. This explains why mature cells such as muscle or nerve cells cannot easily revert to earlier, more flexible states.

At the earliest stages of life, however, cells behave differently. Naïve pluripotent stem cells, the most “stem” of stem cells that exist briefly in the very early embryo, can erase occlusion across their entire genome, restoring the ability of all genes to switch on. This “reset” gives these stem cells the unique capacity to develop into any cell type. But once they advance to a more developed “primed” pluripotent stem cell stage, this reset ability vanishes, and their developmental potential begins to narrow thereafter.

Lahn’s team identified a key player in this resetting process: a protein called Esrrb. Esrrb functions as a de-occlusion factor in naïve stem cells, restoring occluded genes to an activatable state. When Esrrb disappears – as it does when naïve stem cells mature into primed stem cells – the ability to erase occlusion is lost, locking in the gradual loss of flexibility.

Surprisingly, the team found that occlusion can occur through an extraordinarily simple mechanism: genes can become permanently silent just by being wrapped into basic DNA-protein structures called nucleosomes. This suggests that gene occlusion may be a built-in default feature of DNA organization.

In later-stage stem cells, the ability to erase occlusion is lost due to the disappearance of Esrrb. To keep important genes ready to be turned on, these cells use “placeholder” proteins that preserve a gene’s activatable state without actually switching it on.

For example, in neural stem cells, the Sox2 protein protects brain-related genes from being occluded, so they remain capable of being activated when needed. Once differentiation begins, these placeholders disappear. Genes needed in the new cell type can then be activated by downstream factors, while other genes become wrapped up in nucleosomes to become permanently occluded.

By linking the gradual loss of gene flexibility to the way DNA is packaged, Lahn’s research offers a compelling explanation for how multicellular organisms build their diverse cell types from a single starting cell. It may also shed light on why reprogramming cells is so difficult, and how errors in this process can contribute to diseases such as cancer and aging.