SummarySomatic LINE-1 (L1) retrotransposition during neurogenesis is a potential source of genotypic variation among neurons. As a neurogenic niche, the hippocampus supports pronounced L1 activity. However, the basal parameters and biological impact of L1-driven mosaicism remain unclear. Here, we performed single-cell retrotransposon capture sequencing (RC-seq) on individual human hippocampal neurons and glia, as well as cortical neurons. An estimated 13.7 somatic L1 insertions occurred per hippocampal neuron and carried the sequence hallmarks of target-primed reverse transcription. Notably, hippocampal neuron L1 insertions were specifically enriched in transcribed neuronal stem cell enhancers and hippocampus genes, increasing their probability of functional relevance. In addition, bias against intronic L1 insertions sense oriented relative to their host gene was observed, perhaps indicating moderate selection against this configuration in vivo. These experiments demonstrate pervasive L1 mosaicism at genomic loci expressed in hippocampal neurons.
Highlights d Single-cell genomic analysis of hippocampal neurons reveals a somatic L1 insertion d The donor L1 is slightly 5ʹ truncated and lacks a conserved YY1 binding site d Young L1s with truncated or mutated YY1 binding sites are globally hypomethylated d L1 is able to mobilize in the brain because of locus-specific exceptions to repression
Mobilization of retrotransposons to new genomic locations is a significant driver of
mammalian genome evolution, but these mutagenic events can also cause genetic
disorders. In humans, retrotransposon mobilization is mediated primarily by proteins
encoded by LINE-1 (L1) retrotransposons, which mobilize in pluripotent cells early in
development. Here we show that TEX19.1, which is induced by developmentally
programmed DNA hypomethylation, can directly interact with the L1-encoded protein
L1-ORF1p, stimulate its polyubiquitylation and degradation, and restrict L1
mobilization. We also show that TEX19.1 likely acts, at least in part, through
promoting the activity of the E3 ubiquitin ligase UBR2 towards L1-ORF1p. Moreover,
loss of Tex19.1 increases L1-ORF1p levels and L1 mobilization in
pluripotent mouse embryonic stem cells, implying that Tex19.1
prevents de novo retrotransposition in the pluripotent phase of the
germline cycle. These data show that post-translational regulation of L1
retrotransposons plays a key role in maintaining trans-generational genome stability
in mammals.DOI:
http://dx.doi.org/10.7554/eLife.26152.001
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