R-loop landscapes in the developing human brain are linked to neural differentiation and cell type-specific transcription [hiPSC-derived neuron DRIP-seq]

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, we conclude that R-loops are important for fine-tuning differentiation-sensitive gene expression programs of neural progenitor cells.