The role of R-loops, three-stranded nucleic acid structures harboring DNA:RNA hybrids, in regulating cell fate decisions remains elusive. Using an isogenic human stem cell platform, we systematically characterized R-loops, DNA methylation, histone modifications, and chromatin accessibility in pluripotent cells and their lineage-differentiated derivatives. We found that R-loops initially formed co-transcriptionally at pluripotency genes in pluripotent cells. Upon differentiation into neural, mesenchymal, endothelial, and smooth muscle lineages, R-loops and repressive chromatin marks increased synergistically on pluripotency genes and undesired lineage genes, while new R-loops formed co-transcriptionally to activate lineage determination genes. In reprogrammed pluripotent cells, features of epigenetic memory and aberrant gene expression were initially present in regions highly enriched with R-loops, but became resolved with serial passaging. Our analysis defines a multi-faceted role of R-loops in cell fate determination and adds an additional layer of epigenetic control of cell state changes and cell fate memory. SOURCE: Zunpeng Liu (zunpengliu@163.com) - Jing Qu State Key Laboratory of Stem Cell and Reproductive Biology

Pluto Bioinformatics

GSE145964: Genome-wide R-loop landscapes during epigenetic programming and reprogramming