Pre-mitotic genome re-organisation bookends the B cell differentiation process

Wing Fuk Chan,Christine R Keenan,Hannah D Coughlan,Rhys S Allan,Timothy M Johanson,Gordon K Smyth,Philip D Hodgkin,Naiara G Bediaga,Jie H S Zhou

doi:10.1038/s41467-021-21536-2

Wing Fuk Chan, Christine R Keenan + Show 7 more

Open Access

https://doi.org/10.1038/s41467-021-21536-2

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Abstract

During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation to cell cycle, division and time in response to cellular activation and differentiation signals has yet to be explored, although it has been proposed to occur during DNA synthesis or after mitosis. Here, we elucidate the chromosome conformational changes in B lymphocytes as they differentiate and expand from a naive, quiescent state into antibody secreting plasma cells. We find gene-regulatory chromosome reorganization in late G1 phase before the first division, and that this configuration is remarkably stable as the cells massively and rapidly clonally expand. A second wave of conformational change occurs as cells terminally differentiate into plasma cells, coincident with increased time in G1 phase. These results provide further explanation for how lymphocyte fate is imprinted prior to the first division. They also suggest that chromosome reconfiguration occurs prior to DNA replication and mitosis, and is linked to a gene expression program that controls the differentiation process required for the generation of immunity.

Highlights

During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity
By performing a fine spatiotemporal analysis of B-cell activation, we reveal that the changes to 3D chromatin structure occur in two discrete windows, associated with prolonged time in the G1 phase of the cell cycle
As such, using the Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI) system to examine the final stage of B-cell differentiation, we find that as B cells prepare to differentiate into plasmablasts a greater proportion are found in G1, consistent with spending increasing amounts of time at this stage of the cell cycle (Fig. 6a)

Summary

Introduction

During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity When these changes occur in relation to cell cycle, division and time in response to cellular activation and differentiation signals has yet to be explored, it has been proposed to occur during DNA synthesis or after mitosis. These results provide further explanation for how lymphocyte fate is imprinted prior to the first division They suggest that chromosome reconfiguration occurs prior to DNA replication and mitosis, and is linked to a gene expression program that controls the differentiation process required for the generation of immunity. We propose that the 3D genome is reconfigured in response to differentiation signals prior to DNA synthesis and mitosis to ensure the implementation of a transcriptional program required for the generation of B-cell immunity

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