Higher-order chromatin structure regulates gene expression, and mutations in proteins mediating genome folding underlie developmental disorders known as cohesinopathies. However, the relationship between three-dimensional genome organization and embryonic development remains unclear. Here we define a role for bromodomain-containing protein 4 (BRD4) in genome folding, and leverage it to understand the importance of genome folding in neural crest progenitor differentiation. Brd4 deletion in neural crest results in cohesinopathy-like phenotypes. BRD4 interacts with NIPBL, a cohesin agonist, and BRD4 depletion or loss of the BRD4–NIPBL interaction reduces NIPBL occupancy, suggesting that BRD4 stabilizes NIPBL on chromatin. Chromatin interaction mapping and imaging experiments demonstrate that BRD4 depletion results in compromised genome folding and loop extrusion. Finally, mutation of individual BRD4 amino acids that mediate an interaction with NIPBL impedes neural crest differentiation into smooth muscle. Remarkably, loss of WAPL, a cohesin antagonist, rescues attenuated smooth muscle differentiation resulting from BRD4 loss. Collectively, our data reveal that BRD4 choreographs genome folding and illustrates the relevance of balancing cohesin activity for progenitor differentiation.

高阶染色质结构调节基因表达，介导基因组折叠的蛋白质突变是发育障碍的基础，称为黏连蛋白病。然而，三维基因组组织与胚胎发育之间的关系仍不清楚。在这里，我们定义了含溴结构域蛋白 4 (BRD4) 在基因组折叠中的作用，并利用它来了解基因组折叠在神经嵴祖细胞分化中的重要性。BRD4神经嵴缺失会导致粘连病样表型。BRD4 与 NIPBL（一种内聚素激动剂）相互作用，BRD4 耗尽或 BRD4-NIPBL 相互作用的缺失会降低 NIPBL 的占用率，表明 BRD4 可稳定染色质上的 NIPBL。染色质相互作用作图和成像实验表明，BRD4 耗尽会导致基因组折叠和环挤压受损。最后，介导与 NIPBL 相互作用的单个 BRD4 氨基酸的突变会阻碍神经嵴分化为平滑肌。值得注意的是，WAPL（一种粘连蛋白拮抗剂）的缺失可挽救因 BRD4 缺失导致的平滑肌分化减弱。总的来说，我们的数据揭示了 BRD4 编排基因组折叠并说明了平衡黏连蛋白活性与祖细胞分化的相关性。