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RNA Sequencing Data-driven Dissection of Human Plasma Cell Differentiation Reveals New Potential Transcription Regulators

ABSTRACT: Plasma cells play an important role in the adaptive immune system through a continuous production of antibodies. Several hematological disorders result from the malignant transformation of antibody-secreting plasma cells. A clear understanding of the molecular processes underlying human plasma cell differentiation (PCD) will provide greater insight into such pathologies. Here we present a comprehensive, temporal program of gene expression data encompassing human PCD from memory B cells, using RNA sequencing. Our results reveal 6,374 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 regulators and helicases with consistent stage-specific overexpression and potential importance in PCD, including BATF2, BHLHA15/MIST1, EZH2, WHSC1/MMSET and BLM. We have experimentally validated, for the first time, a role for BLM in regulating cell survival and proliferation during human PCD. Taken together, this RNA-seq analysis of PCD temporal stages helped identify co-expressed gene modules with associated up- /down- regulated transcription regulator genes that could represent major regulatory nodes for human plasma cell differentiation. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148924 | GEO | 2021/04/30

REPOSITORIES: GEO

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Project description:Although early developmental processes involve cell fate decisions that define the body axes and establish progenitor cell pools, development does not cease once cells are specified. Instead, most cells undergo specific maturation events where changes in the cell transcriptome ensure that the proper gene products are expressed to carry out unique physiological functions. Pancreatic acinar cells mature post-natally to handle an extensive protein synthetic load, establsih organized apical-basal polarity for zymogen granule trafficking, and assemble gap-junctions to perimt efficient cell-cell communication. Despite significant progress in defining transcriptional networks that control initial acinar cell specification and differentiation decisions, little is know regarding the role of transcription factors in the specification and maintenance of maturation events. One candidate maturation effector is MIST1, a secretory cell-restricted transcription factor that has been implicated in controlling regulated exocytosis events in a number of cell types. Embryonic knock-out of MIST1 generates acinar cells that fail to establish an apical-basal organization, fail to properly localize zymogen granule and fail to communicate intra-cellularly, making the exocrine organ highly suceptible to pancreatic diseases. In an effort to identify the gene expression differences responsible for MIST1 regulating mature acinar properties. We generated a tamoxifen-inducible mouse model where MIST1 expression could be activated in vivoand performed gene expression arrays on wildtype, MIST1-null, and induced MIST1 pancreatic RNA. RNA was isolated from pancreata of 8 week old mice using the Qiagen RNeasy Midi kit. Pancreta of wildtype, MIST1-null, and MIST1-null with a tamoxifen inducible MIST1-expressing transgene were harvested 36 hours post-tamoxifen administration. Therefore, this experiment provides information on steady-state gene expression differences between wildtype and MIST1-null mice as well as immediate gene expression changes induced by MIST1 expression.

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RNA Sequencing Data-driven Dissection of Human Plasma Cell Differentiation Reveals New Potential Transcription Regulators

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