Programmed genomic instability regulates neural transdifferentiation of human brain microvascular pericytes [ATAC-Seq]

The observation that human microvascular pericytes transdifferentiate into neurons provided an opportunity to explore the endogenous molecular basis for lineage reprogramming. Here, we show that abrupt destabilization of the higher-order chromatin topology that chaperones lineage memory of pericytes is driven by transient global transcriptional arrest. This leads within minutes to localized decompression of the repressed competing higher-order chromatin topology and expression of pro-neural genes. Transition to neural lineage is completed by probabilistic induction of R-loops in key myogenic loci upon re-initiation of RNA polymerase activity, leading to depletion of the myogenic transcriptome and emergence of the neurogenic transcriptome. ATAC-seq profiles of Control, and transdifferentiating human primary brain pericytes sampled every 2 min, Technical replicates: 2/group