G-quadruplexes originating from evolutionary conserved L1 elements interfere with neuronal gene expression in Alzheimer’s disease

Roy Hanna, Anthony Flamier, Andrea Barabino and Gilbert Bernier ()
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Roy Hanna: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont
Anthony Flamier: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont
Andrea Barabino: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont
Gilbert Bernier: Stem Cell and Developmental Biology Laboratory, Hôpital Maisonneuve-Rosemont

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract DNA sequences containing consecutive guanines organized in 4-interspaced tandem repeats can form stable single-stranded secondary structures, called G-quadruplexes (G4). Herein, we report that the Polycomb group protein BMI1 is enriched at heterochromatin regions containing putative G4 DNA sequences, and that G4 structures accumulate in cells with reduced BMI1 expression and/or relaxed chromatin, including sporadic Alzheimer’s disease (AD) neurons. In AD neurons, G4 structures preferentially accumulate in lamina-associated domains, and this is rescued by re-establishing chromatin compaction. ChIP-seq analyses reveal that G4 peaks correspond to evolutionary conserved Long Interspersed Element-1 (L1) sequences predicted to be transcriptionally active. Hence, G4 structures co-localize with RNAPII, and inhibition of transcription can reverse the G4 phenotype without affecting chromatin’s state, thus uncoupling both components. Intragenic G4 structures affecting splicing events are furthermore associated with reduced neuronal gene expression in AD. Active L1 sequences are thus at the origin of most G4 structures observed in human neurons.

Date: 2021
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DOI: 10.1038/s41467-021-22129-9

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