B Cell Division Capacity in Germinal Centers Depends on Myc Transcript Stabilization Through m6A mRNA Methylation and IGF2BP3 Functions

Grenov, A. C.; Moss, L.; Edelheit, S.; Cordiner, R.; Schmiedel, D.; Biram, A.; Hanna, J. H.; Heick Jensen, T.; Schwartz, S.; Shulman, Z.

doi:10.1101/2020.09.08.287433

bioRxiv · 10.1101/2020.09.08.287433

B Cell Division Capacity in Germinal Centers Depends on Myc Transcript Stabilization Through m6A mRNA Methylation and IGF2BP3 Functions

Grenov, A. C.·Moss, L.·Edelheit, S.·Cordiner, R.·Schmiedel, D.·Biram, A.·Hanna, J. H.·Heick Jensen, T.·Schwartz, S.·Shulman, Z.

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Abstract

Long-lasting immunity from pathogens depends on the generation of protective antibodies through the germinal center (GC) reaction. The Myc gene produces highly short-lived transcripts which are essential for generation of high-affinity antibodies. mRNA lifetime is regulated by N6-methyladenosine (m6A)-modification of mRNAs through METTL3 activity; however, the role of this machinery in the GC remains unclear. Here, we find that m6A-modification of mRNAs is required for GC maintenance through Myc mRNA stabilization by the atypical m6A-interactor, IGF2BP3. MYC expression, activation of MYC transcriptional programs and cell-cycle progression were diminished in METTL3-deficient GC B cells. METTL3 attenuated Myc-transcript decay and overexpression of MYC in METTL3-deficient GC B cells restored the GC reaction. IGF2BP3 which was induced by CD40-signaling, reinforced MYC expression and MYC-related gene programs in GC B cells. Our findings explain how GC responses are maintained through regulation of Myc-transcript lifetime and expose new targets for manipulation in MYC-driven lymphoma. One Sentence SummaryGerminal centers depend on the m6A-machinery

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Grenov, A. C., Moss, L., Edelheit, S., Cordiner, R., Schmiedel, D., Biram, A., Hanna, J. H., Heick Jensen, T., Schwartz, S., Shulman, Z.. 2020-09-09. B Cell Division Capacity in Germinal Centers Depends on Myc Transcript Stabilization Through m6A mRNA Methylation and IGF2BP3 Functions. https://doi.org/10.1101/2020.09.08.287433

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