Integrative single-cell chromatin and transcriptome analysis of human plasma cell differentiation

• Our results illustrate a complex and dynamic pattern of epigenetic and transcriptomic modifications in early PC genesis.

• Preplasmablasts already undergo epigenetic remodeling related to mature PC together with UPR priming through mTORC1 pathway activation

Plasma cells (PC) are highly specialized cells representing the end stage of B cell differentiation. We have shown that PC differentiation can be reproduced in vitro using elaborate culture systems. The molecular changes occurring during PC differentiation are recapitulated in this in vitro differentiation model. However, a major challenge exists to decipher the spatiotemporal epigenetic and transcriptional programs that drives the early stages of PC differentiation. We combined single cell (sc) RNA-seq and single cell ATAC-seq to decipher the trajectories involved in PC differentiation. ScRNA-seq experiments revealed a strong heterogeneity of the preplasmablastic and plasmablastic stages. Among genes that were commonly identified using scATAC-seq and scRNA-seq, we identified several transcription factors with significant stage specific potential importance in PC differentiation. Interestingly, differentially accessible peaks characterizing the preplasmablastic stage were enriched in motifs of BATF3, FOS and BATF, belonging to the AP-1 transcription factor family, that may represent key transcriptional nodes involved in PCD. Integration of transcriptomic and epigenetic data at the single cell level revealed that a population of preplasmablasts already undergone epigenetic remodeling related to PC profile together with UPR activation and are committed to differentiate in PC. These results and the supporting data generated with our in vitro PC differentiation model provide a unique resource for the identification of molecular circuits that are crucial for early and mature plasma cell maturation and biological functions. These data thus provide critical insights into epigenetic- and transcriptional-mediated reprogramming events that sustain PC differentiation.