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

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.

Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation

“…We note that an analogous factor that re-establishes cell-type specific gene expression in post-mitotic Blineage cells has not been identified. However, recent data suggest that gene expression changes in LPSstimulated B cells are impacted by two discrete phases of chromatin reorganization, first before initial exit from G1, and second coincident with plasma cell differentiation (72). Based on these results we suggest that Notch2 signaling causes MZ B cells to acquire epigenetic modifications that are key for fostering rapid differentiation potential.…”

The gene regulatory network controlling plasma cell function

“…The unique identities of B cells and ASCs are regulated by two mutually antagonistic genetic networks, requiring a profound change in the transcriptional program of a cell transiting between these differentiation states. This irreversible transcriptional switch is facilitated by a reorganization of the chromatin architecture following B cell activation and during the differentiation process 9,10 . We previously performed a comprehensive transcriptional analysis of all aspects of the B cell differentiation process from naïve B cells through to long‐lived BM plasma cells 11 .…”

Survey of activation-induced genome architecture reveals a novel enhancer of Myc

“…The in situ HiC data is available as GEO series GSE147467. The HiC libraries were processed and differential interactions were assessed as previously described 1 .…”