Transposable element-mediated evolutionary expansion of Sox2- and Brn2-binding regulatory modules for mammalian neural-cell differentiation.

Overview

1. Department of Advanced Bioscience, Faculty of Agriculture, Kindai University, 3327-204 Nakamachi, Nara, 631-8505 Japan

Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13059-026-04050-w.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:31969254, at figshare; found in DataCite
• geo:GSE69476, at NCBI GEO; found in the text, “Transcriptome analysis for nearest genes to…”

Data availability

Publicly available next-generation sequencing datasets were obtained from the NCBI Sequence Read Archive (Additional File 1: Table S6). The datasets used in this study are as follows: Sox2 ChIP-seq data in ESC and NPC (PRJNA285791) [50], Brn2 ChIP-seq data in NPC (PRJNA301599) [51], ChIP-seq data for histone modifications (H3K27ac, H3K27me3, H3K36me3, H3K4me1, H3K4me3, H3K9me3) in ESC and NPC (PRJNA34535) [73], and ATAC-seq data in ESC and NPC (PRJNA986429) [76]. Gene expression data for ESCs and NPCs were retrieved from the NCBI GEO (GSE69476 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69476)) [50].

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 2 authors, 8 keywords, 14 MeSH terms, 2 funders, 81 references.

Cite

This paper

Nishihara, H., & Komiya, A. (2026). Transposable element-mediated evolutionary expansion of Sox2- and Brn2-binding regulatory modules for mammalian neural-cell differentiation. Genome biology, 27(1), 114. https://doi.org/10.1186/s13059-026-04050-w

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