MiR-155 epigenetically counteracts hypoxia for mitochondrial fitness during germinal center positive selection

Nakagawa, R.; Llorian-Sopena, M.; Varsani-brown, S.; Chakravarty, P.; Camarillo, J. M.; Barry, D.; George, R.; Blackledge, N. P.; Duddy, G.; Klose, R.; Turner, M.; Calado, D. P.

doi:10.1101/2023.07.31.551250

bioRxiv · 10.1101/2023.07.31.551250

MiR-155 epigenetically counteracts hypoxia for mitochondrial fitness during germinal center positive selection

Nakagawa, R.·Llorian-Sopena, M.·Varsani-brown, S.·Chakravarty, P.·Camarillo, J. M.·Barry, D.·George, R.·Blackledge, N. P.·Duddy, G.·Klose, R.·Turner, M.·Calado, D. P.

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Abstract

To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centres (GCs). Among those, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by relying on oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)-155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Transcriptome examination and mass spectrometry analysis revealed that miR-155 regulates H3K36me2 levels by directly repressing hypoxia-induced histone lysine demethylase, Kdm2a. This is indispensable for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia. The miR-155-Kdm2a interaction is crucial to prevent excessive production of reactive oxygen species and apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity clones, ensuring their expansion and consequently affinity maturation.

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Nakagawa, R., Llorian-Sopena, M., Varsani-brown, S., Chakravarty, P., Camarillo, J. M., Barry, D., George, R., Blackledge, N. P., Duddy, G., Klose, R., Turner, M., Calado, D. P.. 2023-08-02. MiR-155 epigenetically counteracts hypoxia for mitochondrial fitness during germinal center positive selection. https://doi.org/10.1101/2023.07.31.551250

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