Figure 3.

Epigenetic-like switches in NPCs. (A) In NSCs the long interspersed nuclear element 1 (LINE1) is silenced by histone H3K9 trimethylation (red triangles), DNA methylation (filled lollipops), and binding of the methyl-CpG-binding protein 2 (MECP2) in concert with the transcription factor SOX2. Following differentiation into NPCs, SOX2 and MECP2 dissociate and thus facilitate formation of open chromatin together with LINE1 demethylation. Wingless-dependent β-catenin-mediated activation of TCF/LEF TF, possibly in cooperation with the transcriptional regulator YY1, induces LINE1 transcription and active retrotransposition, which persists in mature neurons (ORF2, open reading frame 2; UTR, untranslated region). (B) Somatic de novo insertions in NPCs are maintained as they differentiate into mature neurons with unique genomes. Dependent on developmental stage and temporospatial trajectories such genomic mosaicism can expand from few cells to sizeable populations underlying distinct circuitries and/or structures and ultimately manifest with altered function.