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

• Published in: Cell genomics 2024-08, Vol.4 (8), p.100606, Article 100606
• Main Authors: Titus, Katelyn R., Simandi, Zoltan, Chandrashekar, Harshini, Paquet, Dominik, Phillips-Cremins, Jennifer E.
• Format: Article
• Language: English
• Subjects: Cell Differentiation - genetics; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurons - cytology; Neurons - metabolism; Promoter Regions, Genetic - genetics; Resource; RNA Polymerase II - genetics; RNA Polymerase II - metabolism
• ISSN: 2666-979X; 2666-979X
• DOI: 10.1016/j.xgen.2024.100606

DNA is folded into higher-order structures that shape and are shaped by genome function. The role of 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 (RNA Pol II) 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 progenitor cells (NPCs) and post-mitotic neurons. During hiPSC-to-NPC and NPC-to-neuron transitions, genes changing from RNA Pol II 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 or promoter-promoter loops or when unlooped. Genes transitioning from repression to RNA Pol II initiation exhibit a slight mRNA increase independent of loop status. Our data link cell-specific loops and robust RNA Pol II-mediated elongation during neural cell fate transitions. [Display omitted] •Thousands of loops are lost and gained upon human iPSC differentiation to NPCs/neurons•Elongated genes most often anchor cell-type-specific promoter-enhancer loops•Initiated genes exhibit equal probability of looping versus not looping•Loops anchoring elongated genes are severely disrupted by RNA polymerase II depletion Titus et al. examine the structure-function relationship between chromatin looping and RNA polymerase II-mediated gene expression during human induced pluripotent stem cell differentiation to neural progenitors and post-mitotic neurons. They find that cell-type-specific promoter-enhancer loops strongly correlate with and may be functionally linked to RNA polymerase II elongation.