Summary: New research shows that transposable elements (TEs)—previously labeled “junk” DNA—played a central role in the evolution of the mammalian brain by expanding gene regulatory networks active during neural development.
The study demonstrates that mobile DNA sequences spread binding sites for key transcription factors, expanding regulatory modules that guide stem cells into neuronal lineages. These discoveries may help refine laboratory methods for generating specific neural cell types from stem cells to support research and therapies for neurodegenerative disease.
Key Research Findings
- Regulatory expansion: Researchers identified more than 20,000 TE-derived binding sites for the neural transcription factors Sox2 and Brn2, which are essential for converting stem cells into neurons.
- Specific TE families: Certain TE families, notably MER51 and MER49, acted as vehicles for dispersing regulatory motifs across the genome during primate evolution.
- Cis-regulatory activity: A substantially larger number of TEs display active regulatory functions in neural progenitor cells (NPCs) than in embryonic stem cells (ESCs).
- Two-phase evolutionary model: Brain regulatory architecture appears to have evolved in two stages—an ancient core established in early vertebrates, followed by a later, TE-driven expansion during the evolution of placental mammals and primates.
- Enhancer-like functions: Many TEs acquired enhancer-like activities that help determine the timing and location of gene activation during neuronal commitment.
Source: Kindai University
Researchers led by Dr. Hidenori Nishihara (Associate Professor, Department of Advanced Bioscience, Kindai University) and Atsushi Komiya examined how TEs contribute to gene regulation during the differentiation of human embryonic stem cells into neural progenitor cells. Their work, published in Genome Biology (Volume 27, Article 114, 2026), combines public genomic datasets and chromatin profiling to map TE-associated binding by Sox2 and Brn2 and to test how TE activity shifts as cells commit to neural fates.
Transposable elements are mobile DNA sequences that can insert into different locations of the genome. Although they constitute roughly 30–50% of the mammalian genome, their roles in specific cell types and at particular stages of differentiation have been unclear. This study shows that many TEs harbor binding sites for transcription factors and can act as cis-regulatory modules that influence nearby gene expression during neural development.
Using comparative analyses between ESCs and NPCs, the team mapped Sox2 and Brn2 binding and linked TE presence to dynamic chromatin changes. They found that endogenous retrovirus-derived sequences and other TE families contributed extensively to Sox2- and Brn2-binding landscapes, with simian-specific retrotransposition events particularly expanding these sites in primates.
Chromatin profiling revealed that approximately half of the Sox2- or Brn2-binding TEs show hallmarks of active cis-regulatory sequences. A subset undergoes clear functional transitions—gaining or losing Sox2 binding—during the ESC-to-NPC transition. Genes nearest to NPC-specific Sox2-binding TEs are upregulated and enriched for functions related to neurogenesis, supporting a direct regulatory role in neuronal lineage commitment.
Motif analysis identified at least 24 TE families that contributed to the genome-wide distribution of Sox2 and Brn2 binding motifs. While some core regulatory sites trace back to early vertebrates (including fishes and reptiles), the later TE-driven expansion in placental mammals and primates increased regulatory complexity, producing thousands of additional binding sites—over 3,000 Sox2 and roughly 500 Brn2 sites in NPCs alone.
Taken together, the data support a two-phase model of regulatory evolution: an ancient conserved framework for neuronal development supplemented by a more recent TE-mediated expansion that diversified and refined gene regulatory dynamics in mammals, especially primates.
The principal conclusion is that TE-derived regulatory elements with changing Sox2-binding patterns are actively involved in neuronal lineage commitment. The evolutionary accumulation of these elements, along with their acquisition of enhancer-like functions, likely contributed to the diversification of gene regulation required for complex brain development.
“These findings alter how we view genome evolution and regulation in complex organs such as the brain,” said Dr. Nishihara. Understanding TE-driven regulatory dynamics may inform evolutionary biology, neuroscience, and translational approaches that aim to produce specific neural cell types for research and therapy.
A deeper knowledge of the switches that guide neuronal development could improve strategies to generate defined neuron types from stem cells, with potential implications for treating neurodegenerative disorders.
Funding information
This research was supported by JSPS KAKENHI Grants (25H01308, 22K06338, 25K01110) and JST CREST (JPMJCR20S6), awarded to Hidenori Nishihara.
Key Questions Answered:
A: Transposable elements (TEs) are DNA sequences that can move within the genome. Making up a large portion of mammalian DNA, they can influence gene activity by introducing new regulatory motifs that switch nearby genes on or off.
A: While not a simple cause of intelligence, TE-driven regulatory innovation likely contributed to greater complexity in brain development by dispersing new regulatory instructions that enabled more diversified gene control, particularly during primate evolution.
A: By identifying the regulatory elements that guide stem cells into specific neuron types, researchers can improve protocols for producing those cell types in the lab. Better cell models and potential cell-replacement approaches could ultimately support efforts against neurodegenerative diseases.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by the editorial team.
- Additional contextual information was provided by staff.
About this genetics and brain evolution research news
Author: Tamaki Kasuya
Source: Kindai University
Contact: Tamaki Kasuya – Kindai University
Image credit: 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
Many copies of transposable elements in mammalian genomes can act as enhancers or promoters that regulate gene expression and development. Despite their abundance, the extent to which TEs have been repurposed as regulatory sequences and the cellular contexts in which they function remain incompletely understood. In particular, changes in TE function during cell differentiation are not well characterized.
Results
The authors analyzed human TEs bound by Sox2 and the neuronal factor Brn2 during ESC-to-NPC differentiation. They identified over 20,000 TE copies with Sox2 or Brn2 binding, including ancient SINEs/LINEs and simian-specific endogenous retroviruses, indicating a two-wave evolutionary acquisition. Retrotransposition events involving MER51 and MER49 expanded simian-specific Sox2 and Brn2 binding sites respectively. Epigenetic profiling suggests roughly half of these TE-bound sites act as potential cis-regulatory elements, and a subset shows functional shifts in Sox2 binding during neural differentiation. Genes nearest to NPC-specific Sox2-binding TEs are upregulated and enriched for neurogenesis-related functions.
Conclusions
The accumulation of TE-derived cis-regulatory elements during mammalian evolution likely contributed to the diversification and refinement of gene regulatory dynamics that underlie neuronal development.