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 genomes were depleted of local genomic interactions but enriched for long-range genomic interactions that spanned multiple topologically associating domains. Population-based simulation of spherical and torroid 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 super-contraction. Super-contraction 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. Super-contraction was accompanied by the repositioning of centromeres, pericentromeres and Long-Interspersed Nuclear Elements 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 rDNA and mini-nucleoli to the lamina: a process that was closely associated with sharply reduced rRNA expression. We propose that large-scale chromatin reorganization involving super-contraction and recruitment of heterochromatin and nucleoli to the nuclear lamina facilitate the folding of the neutrophil genome into a confined geometry imposed by a multi-lobed nuclear architecture. Performed in situ Hi-C, GRO-Seq, RNA-Seq, ChIP-Seq and MeDIP-Seq, in combination with 3D-FISH to pinpoint the underlying molecular mechanisms by which diploid genomes fold into a confined geometry imposed by a multi-lobed nuclear architecture.