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bioRxiv · 10.1101/2023.07.18.549494

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.
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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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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.. 2023-07-18. R-loop landscapes in the developing human brain are linked to neural differentiation and cell-type specific transcription. https://doi.org/10.1101/2023.07.18.549494

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