3052 – CLONAL HEMATOPOIESIS-ASSOCIATED DNMT3A HAPLOINSUFFICIENCY CAUSES DICHOTOMOUS DNA METHYLATION DEFECTS AT ENHANCERS IN MATURE HUMAN IMMUNE CELLS

• Published in: Experimental hematology 2021-08, Vol.100, p.S67-S67
• Main Authors: Byun, Minji, Lim, Jung-Yeon, Duttke, Sascha, Baker, Turner, lee, Jihye, Marazzi, Ivan, Benner, Christopher
• Format: Article
• Language: English
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2021.12.270

DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for the acquisition of cellular identity and specialized functions during cellular differentiation. DNMT3A is the most frequently mutated gene in age-related clonal hematopoiesis. As such, mature immune cells harboring DNMT3A mutations can be readily detected in elderly individuals. Most acquired DNMT3A mutations are heterozygous and predicted to cause loss-of-function, indicating that haploinsufficiency is the predominant pathogenic mechanism. Yet, how DNMT3A haploinsufficiency affects the function of mature immune cells is poorly understood. Here, we demonstrate that DNMT3A haploinsufficiency impairs the gain of DNA methylation at decommissioned enhancers, while simultaneously and unexpectedly impairs DNA demethylation newly activated enhancers in mature human myeloid cells. The DNA methylation defects alter the activity of the affected enhancers, leading to abnormal gene expression and impaired immune response. These findings provide insights into the mechanism of immune dysfunction associated with acquired DNMT3A mutations and clonal hematopoiesis.