3034 – CH-ASSOCIATED DNMT3A MUTATIONS MODIFY THE EXPRESSION OF GENES WITH REPRESSIVE HISTONE MARKS

DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for acquiring cellular identity and specialized functions during cellular differentiation. DNMT3A is the most frequently mutated gene in age-related clonal hematopoiesis (CH). DNMT3A-mutated hematopoietic stem and progenitor cells retain their ability to differentiate, giving rise to DNMT3A-mutated differentiated immune cells in circulation and tissues. Previously, we demonstrated that DNMT3A haploinsufficiency causes dichotomous DNA methylation defects at enhancers in human macrophages and alters the expression of a subset of genes involved in immune response and inflammation. Intriguingly, DNA methylation at the promoters of differentially expressed genes remained unchanged in the mutant macrophages, and the molecular link between DNA methylation defects at enhancers and altered gene expression was unclear. Through a deep characterization of chromatin features and mapping of enhancer-promoter interactions, we demonstrate that the genes whose expression is altered in DNMT3A-mutated macrophages are enriched with repressive histone marks that have been shown to cross-talk extensively with DNA methylation. Similar results were obtained from independent model systems including murine models of inducible DNMT3A mutation. These findings provide insights into the mechanism of immune dysfunction associated with CH and acquired DNMT3A mutations.