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

backgroundIn 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.

resultsWe 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.

conclusionsThe 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.