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Nuclear Morphology is Instructed by the Loop Extrusion Program [scRNA-seq]

ABSTRACT: More than a century ago Metchnikoff defined neutrophils as small amoeboid-like cells that harbored peculiar polymorphonuclear structures. While since these early studies much has been learned about neutrophil physiology, mechanistic insight into neutrophil polymorphonuclear assembly remains rudimentary. Here we found that depletion of factors, that initiate the loop extrusion program, including NIPBL and MAU2, greatly accelerated the conversion of mononuclear to polymorphonuclear cells and orchestrated the induction of a neutrophil specific transcription signature. Remarkably, mere ablation of either NIPBL or MAU2 expression under conditions that normally prevent neutrophil differentiation, swiftly converted mono-nuclear into polymorphonuclear cells that expressed a neutrophil specific gene program. Depletion of NIPBL and MAU2 in neutrophil progenitors activated an armamentarium of neutrophil-specific enhancers to establish a neutrophil genome depleted for loop extrusion-induced looping. These observations indicate that extinction of the loop extrusion program converts mononuclear progenitor cells into polymorphonuclear cells and suffices to induce a neutrophil specific program of gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE211819 | GEO | 2024/02/11

REPOSITORIES: GEO

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Project description:Cohesin organizes mammalian interphase chromosomes by reeling chromatin fibers into dynamic loops. "Loop extrusion" is obstructed when cohesin encounters a properly oriented CTCF protein. It has been proposed that transcription relocalizes or interferes with cohesin, and that active transcription start sites function as cohesin loading sites, but how these effects, and transcription in general, shape chromatin is unknown. To determine whether transcription can modulate loop extrusion, we studied cells in which the primary extrusion barriers could be removed by CTCF depletion and cohesin’s residence time and abundance on chromatin could be increased by Wapl knockout. We found evidence that transcription directly interacts with loop extrusion through a novel "moving barrier" mechanism, but not by loading cohesin at active promoters. Hi-C experiments showed intricate, cohesin-dependent genomic contact patterns near actively transcribed genes, and in CTCF-Wapl double knockout (DKO) cells, genomic contacts were enriched between sites of transcription-driven cohesin localization ("cohesin islands"). Similar patterns also emerged in polymer simulations in which transcribing RNA polymerases (RNAPs) acted as "moving barriers" by impeding, slowing, or pushing loop-extruding cohesins. The model predicts that cohesin does not load preferentially at promoters and instead accumulates at TSSs due to the barrier function of RNAPs. We tested this prediction by new ChIP-seq experiments, which revealed that the "cohesin loader" Nipbl co-localizes with cohesin, but, unlike in previous reports, Nipbl did not accumulate at active promoters. We propose that RNAP acts as a new type of barrier to loop extrusion that, unlike CTCF, is not stationary in its precise genomic position, but is itself dynamically translocating and relocalizes cohesin along DNA. In this way, loop extrusion could enable translocating RNAPs to maintain contacts with distal regulatory elements, allowing transcriptional activity to shape genomic functional organization.

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Nuclear Morphology is Instructed by the Loop Extrusion Program [scRNA-seq]

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