Vitamin C Potentiates Plasma Cell Differentiation via TET-mediated DNA Modifications at a Novel Prdm1 Distal Element

Abstract Ascorbate (vitamin C) is an essential micronutrient in humans. Chronic severe ascorbate deficiency results in a condition termed Scurvy with increased susceptibility to infections. How ascorbate affects the immune system at the cellular and molecular levels remained unclear. In this study, we showed that ascorbate is pivotal for the IL-21-dependent differentiation of BLIMP1+ plasma cells. Ascorbate significantly increases the proportion of B cells expressing BLIMP1 upon IL-21 stimulation without affecting the IL-21-STAT3 signaling. As a co-factor for TET DNA 5-methylcytosine oxidases, ascorbate boosters the enzymatic activity of TET, promoting the oxidation of 5-methylcytosines into 5-hydroxymethylcytosine (5hmC), an intermediate for DNA demethylation. Correspondingly, TET2/3 are required for the enhancement of plasma cell differentiation by ascorbate. Using 5hmC enrichment analysis, we identified ascorbate promotes plasma cell lineage via a novel distal element at the BLIMP1/Prdm1 locus. This ascorbate-responsive element (EAR) is normally methylated and is hydroxymethylated in the presence of ascorbate. Notably, the 5hmC-modified CpG exists within the STAT3 binding motif and the pattern is evolutionarily conserved, suggesting the ascorbate-assisted DNA modification is required for STAT3 recruitment to EAR and the subsequent Prdm1 activation. This study provides an example of how micronutrients may influence immune response via epigenetic regulation. Our finding also implies that epigenetic enzymes can function as sensors to gauge the availability of metabolites and influence cell-fate decisions.