Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Francesc Català-Moll, et al.

Sep 04, 2019

Received Date: 16th August 19

Francesc Català-Moll, Dieter Weichenhan, Pavlo Lutsik, Ángel F. Álvarez-Prado, Javier Rodríguez-Ubreva, Christian Klemann, Carsten Speckmann, Hassan Abolhassani, Mónica Martínez-Gallo, Romina Dieli-Crimi, Pere Soler-Palacín, Sven Kracker, Lennart Hammarström, Anne Durandy, Bodo Grimbacher, Christoph
Plass and Esteban Ballestar

Mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although evidences both support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation defects, of which approximately 25% of these defects correspond to active events. For genes that undergo active demethylation that is impaired in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naïve B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature