Gene Number:

1788Location: 2p23.3

Key Functions: De novo DNA methylation, epigenetic regulation, cellular differentiation, hematopoiesis

DNMT3A encodes DNA (cytosine-5)-methyltransferase 3 alpha, one of the primary enzymes responsible for de novo DNA methylation—the process by which new methylation marks are added to previously unmethylated cytosine residues in CpG dinucleotides. This function is crucial during early development and cell differentiation, where DNMT3A helps establish the foundational epigenetic landscape that defines cellular identity and gene expression programs.

Functionally, DNMT3A works in close cooperation with its paralog DNMT3B and regulatory cofactor DNMT3L to shape methylation patterns across the genome. Through the addition of methyl groups to DNA, DNMT3A silences transposable elements, regulates imprinted genes, and orchestrates the expression of lineage-specific transcriptional networks. It plays a particularly pivotal role in hematopoietic stem cells (HSCs), maintaining the balance between self-renewal and differentiation—a process essential for lifelong blood cell formation.

At the molecular level, DNMT3A mutations—especially heterozygous missense or nonsense variants such as the recurrent R882H mutation—disrupt the enzyme’s catalytic activity or dimerization capacity, leading to altered methylation profiles and transcriptional deregulation. These mutations are among the most common somatic lesions in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and clonal hematopoiesis of indeterminate potential (CHIP).

From an epigenetic perspective, impaired DNMT3A function results in global hypomethylation with localized hypermethylation of tumor suppressor loci, promoting oncogenic transformation. Beyond hematologic disease, DNMT3A variants have been implicated in neurodevelopmental disorders such as Tatton-Brown-Rahman syndrome, underscoring its systemic importance in gene regulation.

In essence, DNMT3A acts as a master architect of the epigenome, writing the methylation patterns that define cell fate and developmental potential. Its disruption not only reshapes the methylome but also rewires gene expression networks, linking epigenetic misregulation directly to disease pathogenesis and aging.