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

Germinal center (GC)-B cell proliferation relies on oxidative phosphorylation. Positively selected GC-B cells initiate cell division in the hypoxic light zone (LZ) microenvironment and continue vigorous proliferation upon migration to the dark zone. However, the mechanisms underlying how these GC-B cells reprogram mitochondrial bioenergetic functions to sustain cell division while overcoming hypoxia-driven energy stress are not understood. We found that microRNA (miR)- 155 directly repressed the expression of hypoxia-induced histone lysine demethylase 2a, resulting in fine-tuning of histone H3 di-methylated lysine 36 levels. This regulation optimized the expression of vital nuclear mitochondrial genes in LZ GC-B cells, thereby preventing excessive production of mitochondrial reactive oxygen species and apoptosis. Thus, miR-155-regulated epigenetic mechanisms facilitate dynamic mitochondrial remodeling of LZ GC-B cells.