DNA is folded into sophisticated, complex higher-order patterns within the cell nucleus to establish and maintain cell-type-specific gene-expression programs. These patterns consist of chromosome territories, A/B-type compartments, topologically associated domains (TADs), subTADs, and looping interactions. However, conflicting results have accumulated about the functional role for folding patterns in the regulation of gene expression, highlighting the critical gap in our understanding of the genome’s structure-function relationship. In this thesis, I first provide an overview of mammalian genome folding and my main contributions toward landmark publications in the Phillips-Cremins lab. Then, I investigate how long-range loops and RNA polymerase II (RNA Pol II)-mediated gene expression are linked within the context of human neural lineage commitment. I create genome-wide reference maps of long-range loops, RNA Pol II occupancy, and gene expression during the transitions from human induced pluripotent stem cells (hiPSCs) to neural progenitor cells (NPCs) and NPCs to post-mitotic neurons. I uncover a strong link among cell-type-specific enhancer-promoter loops gained de novo during differentiation, the transition to elongated RNA Pol II from the initiated state, and a robust increase of gene expression. I also demonstrate that loops anchored by elongated genes are particularly sensitive to short-term RNA Pol II perturbation, whereas loops anchored by initiated genes bound by CTCF are protected. In summary, this work uncovers how long-range cell-type specific enhancer-promoter loops play a role in establishment of gene expression programs during human neural lineage commitment.