Comprehensive characterization of neutrophil genome topology.
Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains (TADs). However, neutrophil genomes were enriched for long-range genomic interactions that spanned multiple TADs. Population-based simulation of spherical and toroid genomes revealed declining radii of gyration for neutrophil chromosomes. We found that neutrophil genomes were highly enriched for heterochromatic genomic interactions across vast genomic distances, a process named supercontraction. Supercontraction involved genomic regions located in the heterochromatic compartment in both progenitors and neutrophils or genomic regions that switched from the euchromatic to the heterochromatic compartment during neutrophil differentiation. Supercontraction was accompanied by the repositioning of centromeres, pericentromeres, and long interspersed nuclear elements (LINEs) to the neutrophil nuclear lamina. We found that Lamin B receptor expression was required to attach centromeric and pericentromeric repeats but not LINE-1 elements to the lamina. Differentiating neutrophils also repositioned ribosomal DNA and mininucleoli to the lamina-a process that was closely associated with sharply reduced ribosomal RNA expression. We propose that large-scale chromatin reorganization involving supercontraction and recruitment of heterochromatin and nucleoli to the nuclear lamina facilitates the folding of the neutrophil genome into a confined geometry imposed by a multilobed nuclear architecture.
Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA.
Yina
Y
Zhu
Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
Ke
K
Gong
Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA.
Matthew
M
Denholtz
Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA.
Vivek
V
Chandra
Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA.
Mark P
MP
Kamps
Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
Frank
F
Alber
Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA.
Cornelis
C
Murre
D002454:Cell Differentiation / Q000235:genetics*; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D009504:Neutrophils / Q000166:cytology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000097682:Lamin B Receptor
D004275:DNA, Ribosomal; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor
Lamin B receptor; genome topology; neutrophils; nucleoli; rDNA