RNA-sequencing data-driven dissection of human plasma cell differentiation reveals new potential transcription regulators

Alboukadel Kassambara,Sara Ovejero,Veronika Vikova,Coraline Thibaut,Michel Jourdan,Jérôme Moreaux,Laurie Herviou,Olivier Elemento,Philippe Pasero

doi:10.1038/s41375-021-01234-0

Abstract

Plasma cells (PCs) play an important role in the adaptive immune system through a continuous production of antibodies. We have demonstrated that PC differentiation can be modeled in vitro using complex multistep culture systems reproducing sequential differentiation process occurring in vivo. Here we present a comprehensive, temporal program of gene expression data encompassing human PC differentiation (PCD) using RNA sequencing (RNA-seq). Our results reveal 6374 differentially expressed genes classified into four temporal gene expression patterns. A stringent pathway enrichment analysis of these gene clusters highlights known pathways but also pathways largely unknown in PCD, including the heme biosynthesis and the glutathione conjugation pathways. Additionally, our analysis revealed numerous novel transcriptional networks with significant stage-specific overexpression and potential importance in PCD, including BATF2, BHLHA15/MIST1, EZH2, WHSC1/MMSET, and BLM. We have experimentally validated a potent role for BLM in regulating cell survival and proliferation during human PCD. Taken together, this RNA-seq analysis of PCD temporal stages helped identify coexpressed gene modules with associated up/downregulated transcription regulator genes that could represent major regulatory nodes for human PC maturation. These data constitute a unique resource of human PCD gene expression programs in support of future studies for understanding the underlying mechanisms that control PCD.

Highlights

Representing the end stage of B-cell differentiation, plasma cells (PCs) play an important role in humoral immunity by synthesizing and secreting antibodies, protecting the host against infections [1]
To better understand the nature of the regulatory processes involved in human PC differentiation (PCD), we focused on transcription factors (TFs) and EE genes
Two hundred thirty-seven TF/EE genes are included in one-step-down groups, 49 in the two-step-updown groups, and 36 in the two-step-down-up groups (Fig. 3B and Supplementary Table S7). These results suggest that the specific patterns of gene expression detected during PCD are associated with specific TF/EE gene transcriptional changes

Summary

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Representing the end stage of B-cell differentiation, plasma cells (PCs) play an important role in humoral immunity by synthesizing and secreting antibodies, protecting the host against infections [1]. The differentiation of B cells into PCs is associated with substantial and coordinated changes in gene expression profiles [6]. We have experimentally validated a role of BLM in regulating cell survival and proliferation in PCD Taken together, this analysis identifies a discrete set of genes that function together to regulate PCD. This analysis identifies a discrete set of genes that function together to regulate PCD

Materials and methods

Discussion

Findings

Compliance with ethical standards