Summary: New research reveals that transposable elements (TEs), once dismissed as “non-functional” or “junk” DNA, played a pivotal role in the evolution of the mammalian brain.
The study demonstrates that these mobile DNA sequences expanded gene regulatory networks during neural development by spreading binding sites for critical transcription factors. These insights could refine strategies for generating specific neural cells from stem cells to combat neurodegenerative diseases.
Key Research Findings
- Regulatory Expansion: The study identified over 20,000 TE-derived binding sites for Sox2 and Brn2, two proteins essential for turning stem cells into neurons.
- Specific TE Families: Certain families, such as MER51 and MER49, acted as vehicles to spread regulatory “motifs” across the genome during primate evolution.
- Cis-Regulatory Activity: A substantially larger number of TEs show active regulatory functions in neural progenitor cells (NPCs) compared to embryonic stem cells (ESCs).
- The Two-Phase Model: Brain regulation evolved in two stages: an ancient core framework dating back to early vertebrates (fishes and reptiles), followed by a massive expansion driven by TEs during the evolution of placental mammals and primates.
- Enhancer Functions: Many TEs acquired “enhancer-like” functions, specifically helping to determine when and where nearby genes are activated during neuronal commitment.
Source: Kindai University
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.
Funding information
This study was supported by JSPS KAKENHI Grant Numbers 25H01308, 22K06338, and 25K01110, and by JST CREST Grant Number JPMJCR20S6 all to Hidenori Nishihara.
Key Questions Answered:
A: Transposable elements (TEs) are sequences of DNA that can move to different locations within a genome. While they make up 30–50% of the mammalian genome, they were long considered “junk” until scientists realized they could switch nearby genes on or off.
A: It likely made our brains more complex. By spreading new regulatory instructions across the genome, TEs allowed for more sophisticated and diversified gene control during brain development, particularly during primate evolution.
A: Understanding the exact “switches” that turn a stem cell into a specific type of neuron allows scientists to better grow those cells in a lab. This could lead to more effective cell-replacement therapies for neurodegenerative conditions.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and brain evolution research news
Author: Tamaki Kasuya
Source: Kindai University
Contact: Tamaki Kasuya – Kindai University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Transposable element–mediated evolutionary expansion of Sox2- and Brn2-binding regulatory modules for mammalian neural-cell differentiation” by Hidenori Nishihara & Atsushi Komiya. Genome Biology
DOI:10.1186/s13059-026-04050-w
Abstract
Transposable element–mediated evolutionary expansion of Sox2- and Brn2-binding regulatory modules for mammalian neural-cell differentiation
Background
In mammalian genomes, at least several thousand copies of transposable elements (TEs) may function as enhancers or promoters that regulate gene expression, cellular processes, and development.
However, it is still largely unknown how many TEs have been co-opted into regulatory processes and under which cellular situations they are functional. In particular, few studies have addressed how TE functions change during cell differentiation.
Results
We analyze human TEs bound by the transcription factor Sox2 and by the neuronal transcription factor Brn2 during differentiation of embryonic stem cells into neural progenitor cells (NPC). We identify more than 20,000 copies of Sox2- or Brn2-binding TEs, including ancient SINEs/LINEs and simian-specific endogenous retroviruses, which represents two-wave evolutionary acquisition.
Our results suggest that retrotransposition of the endogenous retroviruses including MER51 and MER49 has expanded the genomic prevalence of the simian-specific binding sites for Sox2 and Brn2, respectively. Epigenetics profiling suggests that approximately half of the Sox2- or Brn2-binding TEs function as potential cis-regulatory sequences, with a subset exhibiting clear functional transitions associated with Sox2 binding and release dynamics during neural cell differentiation.
The nearest genes of NPC-specific Sox2 binding TEs are upregulated and enrich for neurogenesis-related gene ontology terms.
Conclusions
The accumulation of TE-derived cis-regulatory elements during mammalian evolution may have contributed to the diversification and refinement of gene regulatory dynamics underlying neuronal development.
