Mechanisms Behind De Novo Gene Regulation Unveiled in Recent Studies

In a groundbreaking exploration of gene regulation, researchers at Rockefeller University have elucidated the mechanisms governing de novo genes—new genes that emerge spontaneously from previously non-coding stretches of DNA. This research, published in two complementary studies in *Nature Ecology & Evolution* and *Proceedings of the National Academy of Sciences (PNAS)*, reveals how transcription factors and the genomic environment activate these genes and integrate them into cellular networks.

De novo genes, while a small fraction of the overall genetic landscape, are pivotal for understanding evolution, biology, and the etiology of numerous diseases. According to Dr. Li Zhao, head of the Laboratory of Evolutionary Genetics and Genomics at Rockefeller University, “The more we know about de novo regulation, the more information we have about gene expression and regulation itself.” This is particularly relevant for diseases such as cancer, which are associated with rapid genetic dysregulation.

Historically, the existence of de novo genes was only established in recent years. Dr. Zhao’s lab began identifying these genes nearly a decade ago. The interest in their regulation was sparked by a conversation with Torsten Weisel, a Nobel laureate and president emeritus of Rockefeller University, who posed a question regarding how these newly discovered genes are regulated. This inquiry prompted Zhao to investigate the expression patterns of de novo genes.

In the *Nature Ecology & Evolution* study, the research team identified three transcription factors acting as master regulators of de novo gene expression. By analyzing gene expression across hundreds of thousands of cells, they discovered that approximately 10 percent of transcription factors were responsible for the majority of de novo gene regulation. The researchers conducted RNA sequencing on genetically engineered fruit flies, confirming that manipulating the number of these transcription factors resulted in clear changes in gene expression.

The follow-up study published in *PNAS* focused on the genomic neighborhoods surrounding de novo genes, investigating whether these newly formed genes are co-regulated with adjacent, more established genes. The findings indicated that de novo genes often share regulatory elements with neighboring genes, suggesting a collaborative regulatory mechanism. Dr. Zhao emphasized the interconnected nature of both studies, stating, “One talks about how the cellular environment regulates new genes. The other asks how genes work together to regulate one another.”

These combined insights not only clarify the regulatory mechanisms of de novo genes but also offer implications for understanding gene network evolution. Zhao noted, “We cannot say for sure that these transcription factors caused de novo genes to originate, but we've now seen that tinkering with transcription factors can cause significant changes.” This research stands to benefit the study of cancer and other diseases linked to rapid genetic changes, as understanding de novo gene regulation could illuminate broader principles of genetic expression.

As research continues, Zhao anticipates further revelations about how gene networks evolve and the regulatory frameworks that underpin them. “Expression and regulation is more complex than we think. De novo genes may provide a simplistic model that helps us better understand gene expression and evolution,” she concluded. This ongoing investigation not only enhances our understanding of genetic regulation but also opens new avenues for potential therapeutic interventions in genetic disorders and diseases driven by dysregulated gene expression.