Scientists have uncovered evidence supporting a mechanism in which transposable elements (TEs), once considered "non-functional" DNA, may have contributed to the evolution and expansion of gene regulation during neural development. Such insights into the mechanisms regulating the development of neuronal cells in the brain may help inform future strategies for generating specific neural cell types from embryonic stem cells (ESCs).
The TEs are mobile DNA sequences that can insert into different locations in the genome. Although TEs make up 30−50% of the mammalian genome, their roles remain poorly understood, particularly in a cell-type-specific context during cell differentiation, while a very small portion of them sometimes influence whether nearby genes are switched on or off. To address this gap, Dr. Hidenori Nishihara, an Associate Professor at the Department of Advanced Bioscience, Faculty of Agriculture and Agricultural Technology and Innovation Research Institute, Kindai University, Japan, along with Mr. Atsushi Komiya from the same department, explored the contribution of TEs during the differentiation of stem cells into neuronal cells. This study was published in Volume 27, article number 114, of the journal Genome Biology on April 09, 2026.
"We are especially interested in uncovering how these elements may have been brought in during evolution to shape complex biological systems, such as the mammalian brain. By studying these questions, we aim to move beyond the traditional view of 'functional' versus 'non-functional' DNA and instead develop a more integrated understanding of how the genome as a whole contributes to biological function and evolution," said Dr. Nishihara, explaining their motivation for this study.
Gene expression can be enhanced or silenced through the binding of proteins known as transcription factors. To better understand how TEs influence gene regulation during neuronal commitment, the researchers used publicly available genomic data and analyzed human TEs bound by the two transcription factors, Sox2 and Brn2, that are critical for neuronal development. They compared the results from ESCs with those from differentiated neural progenitor cells (NPCs).
The study identified more than 20,000 TE-derived binding sites for Sox2 and Brn2, including endogenous retroviruses that expanded during primate evolution. Among these, specific TE families such as MER51 and MER49 carry binding motifs for Sox2 and Brn2, respectively, helping spread regulatory sequences across the genome.
Chromatin profiling further showed that a subset of Sox2-binding TEs is associated with dynamic changes in Sox2 binding and "cis-regulatory" activity during NPC differentiation, suggesting a role in regulating when and where nearby genes become active. This cis-regulatory activity is observed in a substantially larger number of TEs in NPCs compared to ESCs, with particularly strong contributions from TEs that emerged during the evolution of placental mammals. Motif analyses further indicated that at least 24 TE families contributed to the genome-wide spread of Sox2 and Brn2 binding sites, with many of these elements acquiring enhancer-like functions in NPCs.
Interestingly, a subset of Sox2- and Brn2-binding sites located outside of TEs can be traced back to early vertebrates, including reptiles and fishes, suggesting that the core regulatory framework for neuronal development predates placental mammals. The subsequent spread of TEs across the genome appears to have expanded Sox2- and Brn2-binding cis-regulatory elements during primate evolution, yielding over 3,000 Sox2-binding and 500 Brn2-binding sites in NPCs. Overall, these findings support a two-phase model of TE acquisition during evolution, involving both ancient and more recent expansions that together shaped modern gene regulatory networks.
The key finding of the study is that TE-derived regulatory elements with functional changes in Sox2-binding patterns are involved in neuronal lineage commitment, which was previously unknown. The evolutionary expansion, coupled with the gain of enhancer function, further diversified the gene regulation underlying neuronal formation.
"The findings fundamentally reshape how we interpret genome evolution and regulation, particularly in complex organs such as the brain, with potential implications in evolutionary biology, neuroscience, and medical genomics," said Dr. Nishihara, elaborating on the significance of their findings.
Let us hope a deeper understanding of the gene regulatory dynamics underlying neuronal development will help tackle the rising global challenge presented by neurodegenerative diseases.
