CHICAGO, April 21, 2026 (GLOBE NEWSWIRE) — One of the most fundamental questions in biology is how a single fertilized egg produces the diverse cell types making up the body – from neurons and skin to muscle and blood – that bear the same genetic blueprint but distinct expression patterns. Now, a research team lead by Dr. Bruce Lahn, Chief Scientist of VectorBuilder, has uncovered fundamental mechanisms driving this process. The foundational nature of this work might one day lead to a Nobel Prize.
Lahn’s team developed a powerful new technique called Potency-Seq to measure a gene’s transcriptional potency – defined as 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 stem cells differentiate into specialized cell types, their genome steadily loses transcriptional potency, with growing numbers of genes becoming permanently blocked, or “occluded” as Lahn called it, from responding to their transcription factors (TFs) such that they can no longer express even if TFs that would normally activate these genes are present in cells. Lahn’s group named this process “occlusis”, referring to the progressive and irreversible occlusion of genome transcriptional potency during development, which gradually restricts the lineage potential of differentiating cells. They argued that the most basic definition of a cell type is not so much expression pattern, but rather what genes in the genome are transcriptionally potent versus occluded.
The discovery of occlusis addresses a long-unsolved mystery in developmental biology seen across the tree of life, namely, why stem cells have the flexibility to differentiate into specialized cells such as muscle or nerve, but specialized cells, once formed, cannot dedifferentiate into earlier, more flexible states, nor can they transdifferentiate from one specialized state into another state, despite all these cell types carrying the same set of genetic instructions. The occlusis model argues that this is because stem cells possess greater numbers of transcriptionally potent genes than differentiated cells, and furthermore, different types of differentiated cells possess different sets of transcriptionally potent genes.
Importantly, the study also revealed key molecular mechanisms driving the occlusis process. It showed that at the earliest stage of embryonic development, naïve pluripotent stem cells, the most stem of stem cells, can erase occlusion across their entire genome, restoring the ability of all genes to switch on. This reset gives these naïve stem cells the unique capacity to develop into any cell type. Lahn’s group identified a key gene in this resetting process, Esrrb, which functions as a deocclusion factor in naïve stem cells. Critically, Esrrb expression is turned off once naïve stem cells initiate differentiation, which gives genes the ability to lock in the gradual loss of transcriptional potency in subsequent differentiation.
Surprisingly, the team found that occlusion can occur through an extraordinarily simple mechanism: genes can become permanently silenced just by being wrapped into nucleosomes. This indicates that occlusion is a baseline feature of DNA organization, whereby genes will become occluded by default when not protected by transcription factors. Lahn’s team further showed that in later-stage stem cells where the deocclusion ability is already lost but some silent genes need to retain the potential to turn on upon further differentiation, “placeholder” factors such as Sox2 are used to preserve the transcriptional potency of these genes by counteracting the default effect of nucleosome-mediated occlusion.
“The discovery of occlusis and its underlying molecular mechanisms brings unprecedented clarity to a fundamental question in biology, namely, how development creates diverse cell types in a unidirectional manner,” said Dr. Bruce Lahn. “We believe that evolutionarily, gene occlusion laid the foundation for the emergence of multicellular life because the ability to cement the identities of different cell types in the body through gene occlusion is a prerequisite for a multicellular organism to function properly.”
“Curiously, the paper was rejected by a dozen journals without peer review, and it appeared that most journal editors didn’t understand the study or appreciate its significance,” commented Dr. Lahn. “This is a good example of editor tyranny where the personal tastes and even incompetence of editors have an outsized say in dictating what gets published. Regrettably, the collective wisdom of editorship, or the lack thereof, has driven science into a formulaic state that is often lavishly data-rich but woefully brain-poor.”
“We need to revamp the very foundation of science publishing in order for scientific discoveries to speak on their own merits, and for scientific inquiries to remain a fun and deeply intellectual exercise,” said Dr. Lahn, adding, “and I intend to do just that.”
Dr. Lahn plans to establish a nonprofit foundation to fund labs around the world to study occlusis and its relevance to health. “The mechanism underlying the creation and maintenance of diverse cell identities in multicellular lifeforms is seriously understudied despite being foundational to modern biology. It deserves much more attention from researchers than what it currently gets,” said Dr. Lahn.
Overall, this study offers compelling insights into how multicellular organisms build their diverse cell types from a single starting cell. It may also lead to the understanding of how errors in this process could contribute to aging and diseases such as degeneration and cancer.
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VectorBuilder is a global leader in gene delivery technologies. As a trusted partner in thousands of labs and biotech/pharma companies around the world, VectorBuilder is a one-stop shop for the design, development, and optimization of gene delivery solutions from basic research to clinical applications. Its award-winning Vector Studio is a transformative innovation that allows researchers to easily design and order custom vectors online, freeing them from the tedious work of cloning and packaging vectors in the lab. The global company boasts high-throughput vector production capacity, vast vector and component inventories, one-on-one CRO solutions that include advanced AAV capsid engineering capabilities, and state-of-the-art GMP manufacturing facilities. With leading R&D and CDMO capabilities, the VectorBuilder team strives to provide the most effective gene-delivery solutions and develop innovative tools for life sciences research and genetic medicine.
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