SETD2: A New Frontier in Immune Cell Function and Disease Management
The emerging role of
SETD2 in regulating
immune cell function is shedding light on potential therapeutic strategies for a range of
immune-related diseases. As a key
methyltransferase, SETD2 facilitates the
trimethylation of lysine 36 on histone H3 (H3K36me3), a modification crucial for maintaining
genomic stability and regulating
gene transcription. Recent discoveries indicate that SETD2 not only influences
tumorigenesis but also plays a pivotal role in the
development, differentiation, and function of immune cells.
SETD2's involvement in the
immune system spans across both
innate and
adaptive immunity. It has been found to be essential in the
self-renewal and differentiation of hematopoietic stem cells (HSCs), maintaining a balance critical for
immune homeostasis. The loss of SETD2 in HSCs can lead to
genome instability, increased differentiation towards progenitors, and
HSC exhaustion. This disruption not only impairs immune function but also poses a risk of
malignant transformation.
Within the
innate immune response, SETD2 has a significant impact on
macrophage polarization. It inhibits the
M1 macrophage activation pathway by suppressing
hypoxia-inducible factor 1-alpha (HIF-1α), thereby reducing
inflammatory responses. Conversely, reduced levels of SETD2 are linked to increased
M1 polarization and
glycolytic activity, which could exacerbate conditions like
acute lung injury and
osteomyelitis. Furthermore, SETD2 expression in
mast cells has been shown to mitigate
systemic mastocytosis, where its loss can lead to
advanced forms of the disease.
SETD2 also plays a critical role in the
adaptive immune system, particularly within
T cell development and function. The absence of SETD2 impairs
T cell receptor (TCR) recombination, leading to
developmental arrest and
T cell lymphopenia. Additionally, SETD2 influences the balance between
Treg and Th17 cell differentiation, where it promotes
Treg stability while suppressing
pro-inflammatory Th17 responses. Such regulatory effects are crucial for controlling
autoimmune reactions and maintaining
immune tolerance.
In
B cell biology, SETD2 is indispensable for
immunoglobulin gene rearrangement, crucial for
antibody diversity and
adaptive immunity. Loss of SETD2 leads to
defective V(D)J recombination, hampering
B cell development and predisposing cells to
lymphomagenesis. Moreover,
germinal center B cells with reduced SETD2 function exhibit
impaired DNA damage sensing, promoting
B-cell lymphoma progression.
As research advances, understanding the
mechanistic pathways regulated by SETD2 will unlock new possibilities for therapeutic intervention. Targeting SETD2 could potentially modulate
immune cell functions, offering novel treatments for
autoimmune diseases,
inflammatory conditions, and
hematological malignancies.
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Reference
Longmin Chen, Yuan Zou, Yan Dong, Tian Hong, Qianqian Xu, Jing Zhang, Emerging role of SETD2 in the development and function of immune cells, Genes & Diseases, Volume 12, Issue 6, 2025, 101622,
https://doi.org/10.1016/j.gendis.2025.101622
Funding Information:
National Natural Science Foundation of China 82300929
National Natural Science Foundation of China 82470877
National Natural Science Foundation of China 82100892
Department of Science and Technology of Hubei Province Program Project (China) 2022CFB739
Intramural Research Program of the Central Hospital of Wuhan, Hubei, China 23YJ14
Intramural Research Program of the Central Hospital of Wuhan, Hubei, China 21YJ01
Wuhan Talent Project (China)