Denholtz, M. | bioRxiv Science

bioRxiv2018

An inter-chromosomal transcription hub activates the unfolded protein response in plasma cells

Previous studies have indicated that the transcription signature of antibody-secreting cells is closely associated with the induction of the unfolded protein response pathway (UPR). Here we have used genome-wide and single cell analyses to examine the folding patterns of plasma cell genomes. We found that plasma cells adopt a cartwheel configuration and undergo large-scale changes in chromatin folding at genomic regions associated with a plasma cell specific transcription signature. During plasma cell differentiation, Blimp1 assembles into an inter-chromosomal transcription hub with genes associated with the UPR, biosynthesis of the endoplasmic reticulum (ER) as well as a cluster of genes linked with Alzheimers disease. We suggest that the assembly of the Blimp1-UPR-ER transcription hub permits the coordinate activation of a wide spectrum of genes that collectively establish plasma cell identity.

immunology↗

bioRxiv2017

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. However, neutrophil genomes were enriched for long-range genomic interactions that spanned multiple topologically associating domains. 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 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 (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 mini-nucleoli to the lamina: a process that was closely associated with sharply reduced ribosomal RNA 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.

molecular biology↗