R-loop landscapes in the developing human brain are linked to neural differentiation and cell-type specific transcription
LaMarca, E. A.; Saito, A.; Plaza-Jennings, A.; Hellmich, A.; Fernando, M. B.; Javidfar, B.; Espeso-Gil, S.; Estill, M.; Liao, W.; Townsley, K.; Florio, A.; Ethridge, J. E.; Do, C.; Tycko, B.; Shen, L.; Kamiya, A.; Tsankova, N. M.; Brennand, K. J.; Akbarian, S.
Show abstract
Here, we construct genome-scale maps for R-loops, three-stranded nucleic acid structures comprised of a DNA/RNA hybrid and a displaced single strand of DNA, in the proliferative and differentiated zones of the human prenatal brain. We show that R-loops are abundant in the progenitor-rich germinal matrix, with preferential formation at promoters slated for upregulated expression at later stages of differentiation, including numerous neurodevelopmental risk genes. RNase H1-mediated contraction of the genomic R-loop space in neural progenitors shifted differentiation toward the neuronal lineage and was associated with transcriptomic alterations and defective functional and structural neuronal connectivity in vivo and in vitro. Therefore, R- loops are important for fine-tuning differentiation-sensitive gene expression programs of neural progenitor cells.
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