Summary: New research shows that transposable elements (TEs) — long labeled “junk” DNA — played a crucial role in shaping gene regulation during the evolution of the mammalian brain. These mobile DNA sequences spread binding sites for key transcription factors during neural development, expanding regulatory networks that guide neuronal differentiation. The findings could improve methods for deriving specific neural cell types from stem cells and inform research into neurodegenerative diseases.
Transposable elements are DNA sequences that can move within the genome. Although they account for roughly 30–50% of mammalian genomes, their functional contributions, especially in specific cell types and during differentiation, have been difficult to define. This study investigates how TEs influenced gene regulation as embryonic stem cells (ESCs) commit to neuronal lineages, comparing regulatory landscapes between ESCs and neural progenitor cells (NPCs).
Key Research Findings
- Regulatory expansion: The team identified more than 20,000 TE-derived binding sites for two essential neuronal transcription factors, Sox2 and Brn2.
- Specific TE families: Certain TE families, including MER51 and MER49, acted as vehicles to distribute binding motifs across the genome during primate evolution.
- Cell-type specificity: Far more TEs show active cis-regulatory functions in neural progenitor cells than in embryonic stem cells, indicating dynamic changes during differentiation.
- Two-phase evolutionary model: The regulatory architecture for neuronal development appears to have two layers: an ancient core conserved since early vertebrates, and a later, TE-driven expansion that occurred in placental mammals and primates.
- Enhancer functions: Many TE-derived elements acquired enhancer-like activity in NPCs, helping to determine when and where nearby genes are activated during neuronal commitment.
Source: Kindai University
Led by Dr. Hidenori Nishihara (Kindai University) with collaborator Atsushi Komiya, the study used publicly available genomic and epigenetic data to map Sox2- and Brn2-binding events across human TEs during the transition from ESCs to NPCs. The work was published in Genome Biology (Volume 27, article 114) on April 9, 2026.
The researchers specifically examined how TEs contribute binding sites for transcription factors that direct neuronal fate. They found both ancient TE-derived sequences (SINEs/LINEs) and simian-specific endogenous retroviruses among the 20,000+ binding events. Motif analysis revealed that at least 24 TE families contributed to the genome-wide spread of Sox2 and Brn2 binding sites, and many of these elements act like enhancers in NPCs.
Chromatin profiling and epigenetic marks indicated that roughly half of the Sox2- and Brn2-binding TEs show potential cis-regulatory activity. A notable subset displays dynamic changes in transcription factor binding during differentiation — Sox2 binding is gained or released at specific TE loci as cells progress from ESC to NPC states. Genes nearest to NPC-specific Sox2-binding TEs tend to be upregulated and are enriched for neurogenesis-related functions, linking TE activity to developmental gene expression programs.
Evolutionary analysis supports a two-wave acquisition model: an ancient regulatory core traceable to early vertebrates and a later, TE-driven expansion during the evolution of placental mammals and primates. The later wave introduced thousands of new Sox2- and Brn2-binding sites—over 3,000 Sox2 sites and roughly 500 Brn2 sites in NPCs—that diversified gene regulatory networks underlying neuronal differentiation.
The central conclusion is that TE-derived regulatory elements, some of which changed their Sox2- and Brn2-binding behavior during differentiation, actively participate in neuronal lineage commitment. By gaining enhancer-like functions, these elements contributed to the diversification and refinement of regulatory dynamics required for mammalian brain development.
“We aimed to move beyond the simple functional/non-functional dichotomy and to understand how the whole genome contributes to complex biological systems like the brain,” said Dr. Nishihara. The study’s insights may help improve protocols for generating specific neural subtypes from stem cells, with potential applications in modeling and treating neurodegenerative diseases.
Funding information
This research was supported by JSPS KAKENHI Grant Numbers 25H01308, 22K06338, and 25K01110, and by JST CREST Grant Number JPMJCR20S6, awarded to Hidenori Nishihara.
Frequently Asked Questions
A: “Jumping genes” refer to transposable elements — DNA sequences that can copy or move themselves to new genomic locations. They occupy a substantial portion of mammalian genomes and can influence nearby gene activity.
A: The evidence suggests TEs helped increase regulatory complexity by distributing new binding motifs for transcription factors. This process likely contributed to more sophisticated and diversified gene control during brain development, especially in primates.
A: Mapping the regulatory “switches” that guide stem cells into specific neuronal types can improve laboratory methods for producing those cells. Better cell derivation could support cell-replacement strategies and disease modeling for neurodegenerative conditions.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full.
- Additional context was added by editorial staff.
About this research
Author: Tamaki Kasuya
Source: Kindai University
Contact: Tamaki Kasuya – Kindai University
Image: Image 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. Published in 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 developmental processes. Yet the extent to which TEs have been co-opted into regulatory roles, and how their functions change during cell differentiation, remains incompletely understood.
Results
This study mapped human TEs bound by Sox2 and Brn2 during ESC-to-NPC differentiation and identified more than 20,000 TE copies with binding events. The dataset includes both ancient SINEs/LINEs and simian-specific endogenous retroviruses, indicating a two-wave evolutionary acquisition. Retrotransposition of elements such as MER51 and MER49 expanded simian-specific binding sites for Sox2 and Brn2. Epigenetic profiling suggests that about half of these binding TEs serve as potential cis-regulatory elements, with a subset showing clear, differentiation-associated shifts in Sox2 binding. Genes neighboring NPC-specific Sox2-binding TEs are upregulated and enriched for neurogenesis-related functions.
Conclusions
Accumulation of TE-derived cis-regulatory elements over mammalian evolution likely contributed to the diversification and refinement of gene regulatory dynamics that underlie neuronal development and the increased complexity seen in mammalian brains.