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| Status |
Public on Apr 24, 2022 |
| Title |
YTHDF2 suppresses the plasmablast genetic program and promotes germinal center formation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Antibody-mediated immunity is initiated by B cell interactions with cognate antigen, followed by differentiation into multiple cell subsets, including plasmablast, memory, and germinal center (GC) cells. B cell differentiation trajectories are determined by specific transcription factors, yet very few mechanisms that determine B cell fate at the early stage of the response have been described. Here, we report an epigenetic mechanism that specifically suppresses the plasmablast genetic program and promotes GC B cell fate commitment. Single-cell RNA-seq analysis of antigen-specific B cells revealed activated B cell precursors at the pre-GC stage that express high levels of RNA binding proteins, including YTHDF2, which enhances the decay of methylated transcripts. Ythdf2-deficient B cells exhibited intact proliferation and upregulation of early activation markers in response to antigenic stimulation, whereas differentiation into GC B cells was blocked. Mechanistically, B cells required YTHDF2 to attenuate the plasmablast genetic program during GC seeding, and key transcripts of plasmablast-related genes, including Irf4 and Xbp1, were methylated and bound by YTHDF2. Modulation of YTHDF2-dependent gene expression by YTHDF1 and YTHDF3 was less pronounced, and no functional redundancy of these paralogs in GC seeding was observed. Collectively, this study reveals a novel epigenetic mechanism that specifically directs appropriate B cell fate commitment through post-transcriptional suppression of gene expression.
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| Overall design |
Bulk and single-cell RNAseq of WT/CD23cre and Ythdf2 cKO B18-hi B cells, five days after immunization
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| Contributor(s) |
Grenov AC, Shulman Z, Hezroni H |
| Citation(s) |
35508130 |
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| Submission date |
Nov 29, 2021 |
| Last update date |
Jun 27, 2022 |
| Contact name |
Ziv Shulman |
| E-mail(s) |
ziv.shulman@weizmann.ac.il
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| Organization name |
Weizmann Institute of Science
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| Department |
Department of Immunology
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| Lab |
Shulman
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| Street address |
Herzl St 234
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| City |
Rehovot |
| ZIP/Postal code |
76100 |
| Country |
Israel |
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| Platforms (2) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (25)
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| Relations |
| BioProject |
PRJNA784593 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE189819_Exp1_deseq_results.xlsx |
4.9 Mb |
(ftp)(http) |
XLSX |
| GSE189819_Exp2_deseq_results.xlsx |
8.6 Mb |
(ftp)(http) |
XLSX |
| GSE189819_RAW.tar |
380.9 Mb |
(http)(custom) |
TAR (of CSV, MTX, TDF, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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