The DNMT3A gene provides instructions for creating an enzyme known as DNA methyltransferase 3 alpha. This enzyme helps direct which specific instructions within our DNA are active or inactive at any given time.
The Role of DNMT3A in Gene Regulation
Our bodies rely on a sophisticated system to control how genes are expressed, a process known as epigenetics. Epigenetic modifications alter gene activity without changing the underlying DNA sequence itself. One significant epigenetic mechanism is DNA methylation, which involves adding small chemical tags, called methyl groups, to specific DNA building blocks known as cytosines. This tagging acts as a biological “off switch,” signaling to the cell to silence or reduce the activity of nearby genes.
The DNMT3A enzyme plays a distinct role in establishing these new methylation patterns, a process termed de novo methylation. This differs from “maintenance methylation,” primarily carried out by another enzyme, DNMT1, which simply copies existing methylation patterns during cell division. DNMT3A works in cooperation with other proteins, such as DNMT3L, to place these new methyl tags on DNA, especially on CpG dinucleotides (sequences where a cytosine is followed by a guanine).
DNMT3A’s function is important during embryonic development, establishing initial DNA methylation patterns before birth that are needed for cells to specialize. In adult stem cells, such as hematopoietic stem cells in bone marrow, DNMT3A guides their maturation into different blood cells. Without proper function, these stem cells may not differentiate correctly, impacting the body’s ability to produce healthy, specialized cells.
Connection to Developmental Disorders
When the DNMT3A gene contains faults from birth, known as germline mutations, it can lead to specific developmental disorders. One such condition is Tatton-Brown-Rahman Syndrome (TBRS), also referred to as DNMT3A overgrowth syndrome. This syndrome is caused by new, de novo autosomal dominant mutations in the DNMT3A gene. These genetic changes interfere with the enzyme’s proper function, leading to a disruption in the normal regulation of genes during a child’s development.
Individuals with TBRS experience accelerated growth, with increased stature, head circumference, and weight, sometimes beginning before birth. They also exhibit intellectual disability, ranging from mild to severe, and developmental delays. Distinctive facial features include a round face with thick, horizontal, low-set eyebrows, vertically narrow eyes, and prominent upper central incisors, which become more noticeable during adolescence. Other characteristics can include joint hypermobility, reduced muscle tone, behavioral challenges like those in autism spectrum disorder, and seizures.
Acquired Mutations and Disease
Beyond inherited conditions, mutations in the DNMT3A gene can also arise later in life within specific cells, a phenomenon known as somatic mutation. These acquired changes are not passed down from parents but can contribute to the development of various diseases over time. A prominent example is Acute Myeloid Leukemia (AML), a type of blood cancer where DNMT3A mutations are frequently found.
These mutations are present in approximately 22% to 34% of individuals with newly diagnosed AML, particularly those with an intermediate-risk genetic profile. The presence of DNMT3A mutations in AML is associated with less favorable outcomes and a shorter overall survival for patients. The altered enzyme function can lead to widespread changes in DNA methylation patterns within blood-forming cells, contributing to uncontrolled cell growth and the progression of leukemia.
Another condition linked to acquired DNMT3A mutations is Clonal Hematopoiesis of Indeterminate Potential (CHIP). CHIP is an age-related condition where a small population of blood stem cells acquires mutations, including those in DNMT3A, without immediately causing blood cancer symptoms. DNMT3A mutations account for approximately 50% to 80% of identified CHIP cases. While many individuals with CHIP remain asymptomatic, it does increase the risk of developing future blood cancers by about 0.5% to 1.0% per year. Furthermore, CHIP is associated with an approximate two-fold increased risk of cardiovascular issues, independent of traditional risk factors.
Therapeutic Targeting of DNA Methylation
The understanding of DNMT3A’s role in disease has opened avenues for therapeutic interventions that target DNA methylation pathways. One approach involves the use of drugs known as DNMT inhibitors, also called hypomethylating agents. These medications, which include compounds like azacitidine and decitabine, are primarily used in the treatment of certain cancers, particularly blood disorders such as AML and myelodysplastic syndromes.
These inhibitors work by incorporating themselves into the DNA during cell replication, which then traps and degrades the DNMT enzymes, including DNMT3A. This process helps reverse abnormal methylation patterns that might be silencing genes that suppress tumor growth. By reactivating these silenced genes, DNMT inhibitors restore normal cell growth control and induce programmed cell death in cancer cells. They can also enhance the immune system’s ability to recognize and fight cancer cells, sometimes improving the effectiveness of other cancer therapies.