Cell type-specific loops linked to RNA polymerase II elongation in human neural differentiation

Abstract

DNA is folded into higher-order structures that shape and are shaped by genome function. The role for long-range loops in the establishment of new gene expression patterns during cell fate transitions remains poorly understood. Here, we investigate the link between cell-specific loops and RNA polymerase II (RNAPolII) during neural lineage commitment. We find thousands of loops decommissioned or gained de novo upon differentiation of human induced pluripotent stem cells (hiPSCs) to neural progenitors (NPCs) and post-mitotic neurons. During hiPSC-to-NPC and NPC-to-neuron transitions, genes changing from RNAPolII initiation to elongation are >4-fold more likely to anchor cell-specific loops than repressed genes. Elongated genes exhibit significant mRNA upregulation when connected in cell-specific promoter-enhancer loops but not invariant promoter-enhancer loops, promoter-promoter loops, or unlooped. Genes transitioning from repression to RNAPolII initiation exhibit slight mRNA increase independent of loop status. Our data link cell-specific loops and robust RNAPolII-mediated elongation during neural cell fate transitions. HighlightsO_LIThousands of loops are decommissioned and gained upon human iPSC differentiation to NPCs/neurons C_LIO_LIGenes transitioning from initiated-to-elongated exhibit robust mRNA upregulation when connected in cell type-specific promoter-enhancer loops C_LIO_LIGenes transitioning from repressed-to-initiated exhibit slight increases in mRNA levels independent of loop status C_LIO_LIUpon short-term RNAPolII degradation, loops formed by elongated genes are more severely disrupted than those anchoring initiated genes C_LI