TET2 Emerges as Genetic Switch Driving Inflammatory Monocytes in Asthma

A new study published in Molecular Genetics and Genomics has uncovered a previously hidden chain of molecular events that helps explain why some people’s immune systems respond so violently to asthma triggers. By combining large-scale human genetics, epitranscriptomic mapping, and single-cell sequencing, a research team led by Zun Wang and Siyuan Tang of Ningxia Medical University has identified the gene TET2 as a critical driver of inflammatory activation in monocytes, the white blood cells that help fuel airway inflammation in asthma. The work also reveals how a chemical tag on messenger RNA, known as N6-methyladenosine or m6A, acts as the gatekeeper controlling TET2 production, and it pinpoints the enzyme ALKBH5 as the molecule that removes that tag to unleash the inflammatory response.

Asthma affects hundreds of millions of people worldwide and has long been known to run in families, but the majority of the genetic variants linked to the disease sit in stretches of DNA that do not code for proteins. This so-called missing heritability has frustrated researchers for decades, because it is difficult to know which of these non-coding variants actually change how immune cells behave. The team behind the new study approached the problem from an unusual angle. Rather than asking which variants sit near genes, they asked which variants fall inside or near the chemical docking sites for m6A, the most abundant internal modification found in eukaryotic messenger RNA. These sites are called m6A-SNPs, and emerging evidence suggests they can influence how messenger RNA molecules are read, stabilized, and translated, thereby altering protein output without changing the underlying protein sequence.

To find m6A-regulated genes that matter in asthma, the researchers integrated genome-wide association study data from the UK Biobank, covering both asthma diagnoses and measures of lung function such as forced expiratory volume in one second, forced vital capacity, and peak expiratory flow, with a catalog of m6A-associated variants drawn from the m6AVar database. They then used summary-data-based Mendelian randomization, a statistical framework that borrows genetic variants as instruments to infer whether altered gene expression is a cause or merely a consequence of disease, along with expression quantitative trait loci summary statistics from the Westra and CAGE datasets. This triangulation allowed them to prioritize candidate genes in which genetic variation plausibly changes expression in a way that contributes to asthma risk or impaired lung function.

The analysis converged on TET2, a gene encoding ten-eleven translocation methylcytosine dioxygenase 2, an enzyme best known for its role in DNA demethylation and for its profound influence on innate immune cells. In the study’s genetic models, TET2 was associated not only with asthma susceptibility but also with lung function traits, making it one of the few candidates that satisfied evidence criteria across both disease and physiological endpoints. Importantly, the association passed correction for multiple testing at a false discovery rate threshold, indicating that the signal was unlikely to arise by chance despite the enormous number of variants and genes tested.

Genetic prioritization alone cannot reveal where in the body, or in which cells, the effect takes place, so the team turned to single-cell RNA sequencing of tissue from an ovalbumin-induced mouse model of allergic asthma. This technology profiles the gene expression of thousands of individual cells at once, allowing researchers to map which cell types change their molecular identity as disease develops. The single-cell analysis showed that TET2 was selectively upregulated in monocytes during asthmatic inflammation, and that the monocytes themselves displayed hallmarks of inflammatory activation, including enrichment of pro-inflammatory gene programs and activation of the PI3K signaling pathway, a cellular communication cascade with well-established roles in immune cell survival, migration, and cytokine production. Other immune populations, including T helper cells and tissue-resident memory T cells, showed distinct disease-associated changes, but the monocyte-centered pattern of TET2 upregulation stood out as the most consistent finding linked to the genetic signal.

With TET2 identified as the prime suspect, the researchers moved to mechanistic experiments to determine how the gene is controlled during inflammation. When monocytes were exposed to inflammatory stimulation with lipopolysaccharide, levels of the m6A demethylase ALKBH5 rose. This enzyme chemically removes m6A marks from target messenger RNAs. The team found that inflammatory induction of ALKBH5 led to a reduction in m6A modification of TET2 messenger RNA, which in turn increased TET2 protein levels. Using m6A RNA immunoprecipitation to quantify the modification directly, they confirmed that the m6A mark on TET2 transcript was diminished in the presence of ALKBH5, and that wild-type ALKBH5, but not a demethylase-deficient mutant, produced this effect. The result establishes a concrete regulatory loop: inflammation induces ALKBH5, ALKBH5 strips m6A from TET2 messenger RNA, and more TET2 protein accumulates in the cell.

The downstream consequences were equally clear. Elevated TET2 protein activated PI3K/AKT signaling, measurable by increased levels of phosphorylated AKT, and boosted production of pro-inflammatory cytokines, the chemical messengers that recruit and intensify immune responses in the airways. Crucially, the researchers showed that interrupting the pathway at either end, by knocking down TET2 with small interfering RNA or by suppressing ALKBH5, attenuated both the signaling activation and the cytokine output. These loss-of-function experiments provide the strongest evidence yet that the ALKBH5-m6A-TET2 axis is not merely correlated with monocyte inflammation but is functionally required for it.

The implications of the study reach in several directions at once. For asthma genetics, it offers a concrete example of how a non-coding variant can exert its influence by altering an epitranscriptomic modification site rather than a protein-coding sequence, a mechanism that could explain a meaningful share of the missing heritability in asthma and other immune diseases. For immunology, it adds asthma to the growing list of inflammatory conditions in which RNA methylation dynamically reprograms innate immune cells, and it situates TET2, already famous for its roles in leukemia, cardiovascular disease, and clonal hematopoiesis, at the center of a respiratory inflammatory pathway. The involvement of monocytes is particularly relevant to patients with severe or neutrophilic asthma, in whom steroid responses are often poor and innate immune cells are thought to drive much of the disease burden.

Most tantalizing is the therapeutic possibility. Because ALKBH5 acts upstream of TET2 in this pathway, inhibiting ALKBH5 could, in principle, restore m6A marks on TET2 messenger RNA, reduce TET2 protein levels, and calm the overactive PI3K/AKT-driven inflammatory program in monocytes without broadly suppressing the immune system. The authors caution that their findings rest on genetic association, single-cell profiling, and cell-culture experiments, and that validation in patient samples and animal models will be needed before the ALKBH5-m6A-TET2 axis can be considered a drug target. Nevertheless, the study provides a complete narrative arc, from a population-level genetic signal to a molecular mechanism inside individual immune cells, and it does so with an analytical strategy that other researchers can apply to the many complex diseases whose genetics remain stubbornly unexplained. As the cost of single-cell sequencing falls and catalogs of RNA modification sites continue to expand, the approach demonstrated here is likely to be repeated across a widening range of conditions, potentially converting thousands of obscure genetic associations into actionable biological insights.

Subject of Research: Epitranscriptomic regulation of monocyte inflammatory activation in asthma via the ALKBH5-m6A-TET2 axis and PI3K signaling

Article Title: TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses

Article References: Wang, Z., Wang, Q., Sa, Y., Ma, N., Wang, S., Huang, C., Liu, M., & Tang, S. (2026). TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses. Molecular Genetics and Genomics, 301(1), Article 190. https://doi.org/10.1007/s00438-026-02497-x

Image Credits: AI Generated

DOI: 10.1007/s00438-026-02497-x

Keywords: asthma, TET2, ALKBH5, m6A modification, monocytes, PI3K/AKT signaling, GWAS, m6A-SNP, single-cell RNA sequencing, airway inflammation, epitranscriptomics, genetic susceptibility