Study Finds Cells Use Epigenetic Noise to Shift Their Identity

All cells in the body share the same DNA, yet different cell types selectively activate genes tied to their roles. A study from researchers at the University of Chicago, published in Nature, reveals how this process can deviate through random fluctuations in genome structure. The team found that cells sometimes relax tightly packed DNA in a way that generates “epigenetic noise,” allowing genes reserved for other tissues to be expressed. This flexibility benefits immune training and tissue repair, but it can also be exploited by tumors. 

Andrew Koh, senior author of the study, explained, “We believe that this capacity to change a cell’s identity is underappreciated, and we wanted to investigate the mechanisms underlying how cells are able to change their fates.” Together with lead author Noah Gamble, Koh examined medullary thymic epithelial cells (mTECs), which are capable of expressing genes from across the body. These cells play a vital role in the thymus by exposing developing T cells to proteins from diverse tissues. This process ensures that self-reactive T cells are eliminated, preventing an autoimmune response. 

Using single-cell sequencing, Gamble studied chromatin organization in mTECs. Chromatin, the complex of DNA and proteins, loosens when genes are more likely to be activated. Surprisingly, Gamble observed that high accessibility of chromatin did not directly correlate with gene expression. Instead, variation in accessibility—or “noise”—allowed activation of genes from unrelated tissues, helping T cells refine their ability to distinguish self from non-self. He described these findings by noting that chromatin regions normally kept closed became unusually labile or “jiggly,” broadening the potential gene repertoire.

The researchers further investigated the role of p53, the tumor suppressor known as “the guardian of the genome.” In mTECs, p53 was repressed before epigenetic noise increased. When experimentally reactivated, chromatin stabilized, noise diminished, and tissue-specific gene activation was lost, leading to autoimmune disease as self-reactive T cells escaped deletion. Koh summarized, “Because p53 is downregulated, the cells survive and facilitate this ectopic gene expression to promote the self/non-self discrimination.”

The study also extended into cancer biology. Once p53 was deleted in lung cancer models, chromatin noise enabled tumor cells to activate unusual tissue programs, driving aggressive behavior. Such findings suggest that cancers, like mTECs, exploit randomness in chromatin states. Looking ahead, the researchers aim to determine whether noise similarly contributes to wound healing, reprogramming, and therapies targeting cancer or immune disorders.

“It makes sense that to empower an immune system that uses a random process to recognize virtually any entity in the universe, thymic epithelial cells amplify random noise in the genome to ensure the immune system is focused on pathogens and cancers and not its own tissues. It's fighting fire with fire,” Gamble said. “The moral of the story is that sometimes the random background noise can be just as important as the signal.”