Nuclear morphology is shaped by loop-extrusion programs

• 成果类型: Article
• 署名作者: Patta, Indumathi; Zand, Maryam; Lee, Lindsay; Mishra, Shreya; Bortnick, Alexandra; Lu, Hanbin; Prusty, Arpita; McArdle, Sara; Mikulski, Zbigniew; Wang, Huan-You; Cheng, Christine S.; Fisch, Kathleen M.; Hu, Ming; Murre, Cornelis
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; Cleveland Clinic Foundation; La Jolla Institute for Immunology; University of California System; University of California San Diego; University of California System; University of California San Diego
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4639
• DOI: 10.1038/s41586-024-07086-9
• 发表日期: 2024-03-07
• 页码: 196-+
• 关键词: enrichment analysis; web server; gene; cohesin; genome; mutations; chromosomes; principles; package

摘要

It is well established that neutrophils adopt malleable polymorphonuclear shapes to migrate through narrow interstitial tissue spaces(1-3). However, how polymorphonuclear structures are assembled remains unknown(4). Here we show that in neutrophil progenitors, halting loop extrusion-a motor-powered process that generates DNA loops by pulling in chromatin(5)-leads to the assembly of polymorphonuclear genomes. Specifically, we found that in mononuclear neutrophil progenitors, acute depletion of the loop-extrusion loading factor nipped-B-like protein (NIPBL) induced the assembly of horseshoe, banded, ringed and hypersegmented nuclear structures and led to a reduction in nuclear volume, mirroring what is observed during the differentiation of neutrophils. Depletion of NIPBL also induced cell-cycle arrest, activated a neutrophil-specific gene program and conditioned a loss of interactions across topologically associating domains to generate a chromatin architecture that resembled that of differentiated neutrophils. Removing NIPBL resulted in enrichment for mega-loops and interchromosomal hubs that contain genes associated with neutrophil-specific enhancer repertoires and an inflammatory gene program. On the basis of these observations, we propose that in neutrophil progenitors, loop-extrusion programs produce lineage-specific chromatin architectures that permit the packing of chromosomes into geometrically confined lobular structures. Our data also provide a blueprint for the assembly of polymorphonuclear structures, and point to the possibility of engineering de novo nuclear shapes to facilitate the migration of effector cells in densely populated tumorigenic environments.