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

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.

Plasma cell survival: The intrinsic drivers, migratory signals, and extrinsic regulators

“…The ASC fate is overseen by a core triad of transcription factors, BLIMP1, IRF4, and XBP1, while the B cell identity is guided by PAX5, BACH2, and BCL6. Additional transcription factors have been reported such as Aiolos, 61 ZBTB20, 62 and BATF2 and BLM, 63 but BLIMP1, IRF4, and XBP1 are the core factors needed to build an ASC. These factors and their activities have been discussed extensively elsewhere, 60,64 and hence, we only provide a brief summary and discuss their potential role in ASC survival.…”

Transcription/Replication Conflicts in Tumorigenesis and Their Potential Role as Novel Therapeutic Targets in Multiple Myeloma

“…It was shown in vitro that Top1 stimulates BLM unwinding activity on RNA:DNA hybrids, and reciprocally, BLM stimulates Top1 activity on DNA:RNA hybrids, in a helicase activityindependent manner [177]. More recently, RECQ DNA helicase BLM was shown to be overexpressed in prePBs during B to PC differentiation [178]. BLM could restrain the deleterious consequences of R-loop mediated replication stress in highly proliferative prePB cells upon activation of transcription.…”

“…BLM could restrain the deleterious consequences of R-loop mediated replication stress in highly proliferative prePB cells upon activation of transcription. In the absence of BLM, these cells would, therefore, accumulate stalled forks leading to chromosome breaks due to their inability to efficiently remove R-loops and G4 structures [178].…”

Single‐cell resolution of plasma cell fate programming in health and disease

“…The amount of multi-omic data collected over terminal B-cell differentiation has been growing because of high-throughput sequencing technology. Classical time-series transcriptome analyses from various systems modeling PC differentiation in human [43][44][45][46] and in the mouse system [47] revealed a differentiation continuum of gene expression changes. However, to date, only few genes important in initiating and controlling the transitions and progression of naive B cell to early PC precursors have been described.…”