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PubMed2026

Age as a core disease modifier: Distinct clinical, molecular and prognostic landscapes of essential thrombocythaemia in adolescents and young adults.

Essential thrombocythaemia (ET) in adolescents and young adults (AYA, 15-39 years) is a distinct entity with an incompletely defined prognosis. In this multicentre retrospective study, 1728 ET patients from 29 centres across China were stratified into AYA (n = 328) and non-AYA (≥40 years, n = 1400) cohorts. We compared their clinical profiles, genomic landscapes, long-term outcomes and risk factors for progression to post-ET myelofibrosis (MF). AYA patients had fewer cardiovascular risks and lower thrombosis rates, but higher rates of extreme thrombocytosis. Molecularly, AYA patients were enriched for calreticulin (CALR) mutations, whereas Janus kinase 2 (JAK2) predominated in older patients. The burden of non-driver mutations (tet methylcytosine dioxygenase 2 [TET2], DNA methyltransferase 3A [DNMT3A], ASXL transcriptional regulator 1 [ASXL1], SH2‑B adaptor protein 3 [SH2B3]) was lower in AYA patients. Consequently, AYA patients achieved superior long-term outcomes across all key survival endpoints, including overall, myelofibrosis-free and leukaemia-free survival. Analysis of post-ET MF progression risks identified age-specific patterns: CALR mutations are enriched in younger patients and show an age-specific association with MF progression. AYA-ET constitutes a unique clinicomolecular subtype with a favourable prognosis, supporting age-stratified management. The enrichment of CALR mutations and their specific link to MF progression in young patients underscore the urgent need for targeted therapies against CALR-mutant clones.

adolescents and young adults (AYA)↗

PubMed2025

Clonal Hematopoiesis and Risk of New-Onset Myocarditis and Pericarditis.

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of hematopoietic stem cells with leukemia-associated mutations. Certain CHIP mutations promote atherosclerosis and heart failure through immune-related pathways. OBJECTIVE: To test whether CHIP is associated with the development of myocarditis and pericarditis. DESIGN, SETTING, AND PARTICIPANTS: This observational population-based cohort study used data from the UK Biobank. Enrollment occurred between 2006 and 2010. Participants with whole-exome sequencing, no prevalent cardiovascular disease or hematological malignancy, and complete covariate data were included. Follow-up occurred for a median of 13.6 (IQR, 12.8-14.2) years. Analyses were conducted from November 2024 to July 2025. EXPOSURES: Any CHIP (variant allele frequency [VAF] ≥2%) and large CHIP (VAF ≥10%) constituted coprimary study exposures. Secondary analyses considered DNMT3A and TET2 CHIP as separate exposures. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of incident myocarditis and pericarditis. Cox regression tested associations of CHIP with myocarditis and pericarditis, adjusting for age, sex, race and ancestry, and cardiovascular risk factors. Secondary analyses considered myocarditis and pericarditis as separate outcomes. Additional analyses compared associations of CHIP with myocarditis and pericarditis with those with other cardiovascular diseases, and tested the bidirectional associations between CHIP and noncardiac immune-mediated inflammatory diseases. RESULTS: Among 335 426 participants (mean age, 56.1 years; 185 429 female [55.3%] and 149 997 male [44.7%]), 11 057 had any CHIP (3.3%), 7271 had large CHIP (2.2%), and 382 developed myocarditis or pericarditis (0.11%). Any and large CHIP were associated with multivariable-adjusted hazard ratios of 1.75 (95% CI, 1.14-2.68; P = .01) and 2.07 (95% CI, 1.28-3.33; P = .003), respectively, for the primary composite outcome of incident myocarditis and pericarditis. Increased risks were observed for DNMT3A and TET2 CHIP, with hazard ratios of 2.22 (95% CI, 1.17-4.21; P = .01) for DNMT3A with pericarditis and 3.65 (95% CI, 1.16-11.49; P = .03) for TET2 with myocarditis. CHIP associated with myocarditis and pericarditis more strongly than with other cardiovascular diseases (eg, coronary artery disease and heart failure). Any CHIP was also associated with 1.27-fold risk (95% CI, 1.16-1.39; P < .001) of developing noncardiac immune-mediated inflammatory diseases, without evidence for reverse causation. CONCLUSIONS AND RELEVANCE: In this study, CHIP was a strong risk factor for myocarditis and pericarditis among middle-aged adults. Targeting CHIP and its downstream pathways may represent a strategy for preventing or treating pericarditis and myocarditis.

Adult↗

PubMed2026

Clonal Hematopoiesis and Incident Heart Failure.

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with acquired preleukemic variants, has been associated with cardiometabolic diseases, including heart failure (HF). However, prior studies have lacked power to examine less common CHIP driver variants and have not investigated potential mediators of the CHIP-HF association. OBJECTIVE: To test whether specific CHIP subtypes are associated with incident HF and determine the extent to which CHIP-associated comorbidities mediate this association. DESIGN, SETTING, AND PARTICIPANTS: This was a UK Biobank prospective population-based cohort study of community-dwelling adults in the UK, with enrollment from 2006 to 2010 and follow-up through 2020. Included were participants with whole-exome sequencing (WES) and without prevalent HF, hematologic malignancy, or other CHIP-associated comorbidities (coronary artery disease [CAD], atrial fibrillation [AF], type 2 diabetes [T2D], or chronic kidney disease [CKD]) at baseline. Study data were analyzed from April through October 2025. EXPOSURES: Presence of CHIP and gene-specific CHIP subtypes (DNMT3A, non-DNMT3A, TET2, ASXL1, JAK2, DNA damage repair genes, and spliceosome genes). Mediation analyses examined CHIP-associated comorbidities (CAD, AF, T2D, and CKD). MAIN OUTCOMES AND MEASURES: The primary outcome was incident HF. Cox regression tested associations of CHIP and CHIP subtypes with incident HF, adjusted for age, sex, race, and cardiovascular risk factors. RESULTS: Among 417 616 participants (mean [SD] age, 56.1 [8.1] years; 234 868 female [56.2%]), 7183 (1.7%) developed incident HF over a median (IQR) of 11.1 (10.4-11.8) years of follow-up. CHIP was associated with HF risk (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.15-1.40; P < .001), driven by non-DNMT3A subtypes (aHR, 1.52; 95% CI, 1.33-1.75; P < .001), including associations with TET2, ASXL1, JAK2, and spliceosome CHIP. DNMT3A CHIP was more modestly associated with HF (aHR, 1.15; 95% CI, 1.00-1.31; P = .04). In mediation analyses, development of CAD, AF, T2D, and/or CKD collectively accounted for 28.2% of the association (95% CI, 11.6%-45.4%; P = .001) between non-DNMT3A CHIP and HF. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that CHIP, especially non-DNMT3A CHIP, was associated with incident HF. Other CHIP-associated comorbidities explained only a minority of the association between non-DNMT3A CHIP and HF. These findings suggest that CHIP is an HF risk factor and potential therapeutic target.

Adult↗

PubMed2026

Paternal exposure to polystyrene nanoplastics induces inter- and transgenerational bronchopulmonary dysplasia-like damage in male offspring by FtMt hypermethylation-mediated ferroptosis.

Bronchopulmonary dysplasia (BPD) is a major cause of chronic lung disease in both preterm infants and adults, but its etiology remains incompletely understood. In this study, F0 generation mice were exposed to polystyrene nanoplastics (PS-NPs), and F1 to F3 generations were obtained by breeding. Multi-omics sequencing including whole genome methylation sequencing, single cell transcriptome sequencing and transcriptome sequencing was performed on the lungs of offspring. The levels of Fe2+, lipid peroxidation products and key gene expression were determined. Male mice exposed to PS-NPs at environmentally relevant doses produced offspring (F1 and F2) that exhibited a typical BPD-like phenotype. Meanwhile, the F0 males showed diminished sperm motility, demonstrating that paternal PS-NPs exposure constituted an etiological factor for BPD in descendants. Mechanistic studies showed that PS-NPs exposure upregulated the expression of DNA methyltransferase Dnmt3a, leading to global hypermethylation of the sperm genome. Importantly, the hypermethylated promoter signature of the mitochondrial ferritin (FtMt) gene partially resisted epigenetic reprogramming and was transmitted to the lungs of offspring, resulting in persistently low FtMt expression in F1 and F2 lungs. This led to increased intracellular Fe2+ levels, subsequently triggered ferroptosis in alveolar epithelial cells, and ultimately impaired alveolarization. Knockdown of FtMt confirmed that FtMt deficiency was sufficient to induce ferroptosis and BPD-like lung injury both in vitro and in vivo. Furthermore, using in vitro fertilization of F0 sperm combined with Dnmt3a siRNA microinjection, we directly demonstrated that Dnmt3a is a key driver for FtMt to escape reprogramming and maintain its hypermethylation. In summary, this study reveals for the first time that paternal PS-NPs exposure causes BPD through a Dnmt3a-FtMt hypermethylation intergenerational and transgenerational axis, providing an epigenetic basis for understanding paternal derived chronic lung disease and potential targets for early intervention.

Animals↗

PubMed2026

The landscape of clonal hematopoiesis of indeterminate potential in long-term breast cancer survivors.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) can confound blood-based genomics and may be shaped by cytotoxic therapy; clarifying its persistence after breast-cancer chemotherapy is relevant for long-term survivorship follow-up. PATIENTS AND METHODS: Buffy-coat whole-exome sequencing was performed in 189 stage I-III breast-cancer survivors with blood collected a median 136.5 months after diagnosis. CHIP was assessed using a prespecified 100-gene hematopoietic-driver compendium and exome-wide interrogation. Clinical associations were assessed with univariable tests and multivariable logistic regression including chemotherapy, radiotherapy, age, smoking and obesity. RESULTS: Within the 100-gene compendium, 54/189 (28.6%) patients harbored ≥1 variant, predominantly missense, with DNMT3A and TET2 predominating and multi-hit cases rare. In multivariable models, chemotherapy was not associated with panel-defined CHIP (OR 0.77; 95% CI 0.40-1.48; p = 0.432). Similarly, age, adjuvant radiotherapy, obesity and smoking status were not significantly associated with panel-defined CHIP. Gene-level comparisons showed no differences by chemotherapy exposure. Exome-wide, 67/189 (35.4%) patients carried ≥1 variant; chemotherapy was not associated with exome-wide variant positivity (OR 0.89; 95% CI 0.48-1.67; p = 0.721), and no locus differed between chemotherapy-exposed and never-exposed women. CONCLUSION: Buffy-coat WES performed in long-term breast cancer survivors shows no cohort-level association between prior chemotherapy and increased CHIP.

Humans↗

PubMed2026

Integrated GWAS and methylation analysis identify DNMT3A as an important regulator of growth in rabbits.

The parameters of individual growth curve can serve as pseudo-phenotype for genetic evaluation in livestock. In this study, we compared five nonlinear growth models using post-weaning body weights of 706 New Zealand White rabbits. Under the best-fitting model, two parameters of mature weight and maturity rate were subjected to GWAS through single-step genomic BLUP framework that integrated phenotypic records from non-genotyped animals with 41,359 SNPs genotyped in 198 individuals. Association analysis identified 147 relevant genomic regions, and also highlighted DNMT3A as a promising candidate gene for further functional investigation. siRNA-mediated knockdown of DNMT3A significantly impaired myoblast proliferation. Whole-genome bisulfite sequencing of DNMT3A-knockdown myoblasts identified 69,480 differentially methylated regions (DMRs). Integrative analyses revealed substantial overlap between DMR-associated genes and GWAS candidate genes, with significant enrichment in vitamin B6 and tyrosine metabolism pathways. These findings suggest that DNMT3A may regulate rabbit growth via mediating DNA methylation of downstream genes.

Animals↗

PubMed2026

Multidomain interaction governs the filamentous assembly of the dominant-negative DNMT3A R882H mutant.

DNA methyltransferase DNMT3A-mediated de novo DNA methylation is important for proper regulation of gene expression and genomic stability in development. The DNMT3A R882H (DNMT3AR882H) mutation, a hot-spot mutation in acute myeloid leukemia and developmental disorders, exerts a dominant-negative effect in DNMT3A-mediated DNA methylation through promoting high-order protein assembly. However, due to the lack of structural knowledge on DNMT3A homo-oligomers, the mechanism behind wild-type DNMT3A (DNMT3AWT) and DNMT3AR882H polymerization remains unclear. Here, we report the single-particle cryo-EM structures of homo-oligomeric DNMT3AWT and filamentous DNMT3AR882H, revealing the role of the regulatory Pro-Trp-Trp-Pro (PWWP) and ATRX-DNMT3-DNMT3L (ADD) domains of DNMT3A in their dynamic assembly. While the oligomeric assembly of DNMT3A is mainly driven by the well-characterized oligomer interfaces in the methyltransferase domain, the autoinhibitory interaction of the PWWP and ADD domains in DNMT3A places them in a position for intermolecular contact, thereby contributing to the filamentous assembly of DNMT3AR882H. Disrupting the autoinhibitory interaction facilitates the transition of DNMT3AR882H polymer toward the low-order oligomeric assembly, reinforcing the aggregation-attenuation effect of the previously characterized oligomer-interface mutation R676K. Together, this study uncovers a multidomain cooperated assembly mechanism for DNMT3A, with important implication in development of effective therapeutic strategies against DNMT3AR882H-associated diseases.

DNA (Cytosine-5-)-Methyltransferases↗

PubMed2026

Loss of Function Dnmt3a Mutation Leads to Aberrant Neutrophil Migration.

Clonal hematopoiesis (CH), an age-related expansion of somatically mutated hematopoietic clones, is associated with increased risk of severe infections including coronavirus disease (COVID)-19, yet the underlying mechanisms remain unclear. Here, we investigated the impact of Dnmt3a deficiency in a murine model of influenza A virus (IAV) pneumonia. Dnmt3a-deficient mice exhibited increased pulmonary viral burden and reduced neutrophil accumulation in IAV-infected lungs despite comparable circulating neutrophil numbers. Functional analyses of neutrophils showed impaired chemotactic migration in vitro, whereas maturation, antimicrobial enzyme content, and metabolic capacity were unchanged. Transcriptomic profiling revealed downregulation of pathways involved in chemotaxis, cytokine signaling, and cellular activation, including reduced expression of Cxcr1. Supporting the translational relevance of these findings, proteomic analysis of plasma from individuals with germline DNMT3A mutations (Tatton-Brown-Rahman syndrome) revealed alterations in proteins associated with cell migration and cytoskeletal dynamics. Collectively, our findings demonstrate that Dnmt3a loss compromises innate immune defense by impairing neutrophil migration in a cell-intrinsic manner, leading to ineffective pathogen clearance. This work provides mechanistic insight into how CH-associated mutations contribute to age-associated susceptibility to infection and highlights altered leukocyte trafficking as a potential therapeutic target in aging populations with CH.

Animals↗

PubMed2025

Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity.

DNMT3A is a critical regulator of hematopoietic stem cell (HSC) fate decisions and the most recurrently mutated gene in human clonal hematopoiesis (CH). DNMT3A is described as a DNA methyltransferase enzyme, but cells with DNMT3A loss of function show minor changes in DNA methylation that do not correlate with altered gene expression. To explore the possibility that Dnmt3a has DNA-methylation-independent functions in HSCs, we created an allelic series of mice with varying levels of DNA-methylation-impaired Dnmt3a. Clonal expansion of Dnmt3a-deficient HSCs was rescued by Dnmt3a proteins lacking DNA methylation capacity, suggesting that Dnmt3a has important non-canonical functions in HSCs. Dnmt3a-null HSCs can be transplanted indefinitely, implying the ability to circumvent mechanisms that limit the replicative lifespan of HSCs, such as telomere shortening. Dnmt3a-null HSCs show increased telomerase activity and sustain telomere length over serial transplantation, revealing a previously unidentified role for DNMT3A mutations in regulating HSC longevity that is unrelated to DNA methylation function.

Animals↗

PubMed2020

LINC00922 regulates epithelial-mesenchymal transition, invasive and migratory capacities in breast cancer through promoting NKD2 methylation.

Breast cancer ranks as the major reason for mortality in women populations, accounting for 23% of all cancer deaths. One in every three Asian women encounters the risk of this cancer in their lifetime. Long intergenic non-coding RNAs (lincRNAs) have emerged as tumor promoters and suppressors. The molecular mechanism of breast cancer remains elusive. Therefore, the current study aimed to explore the role lincRNA LINC00922 plays in the development of breast cancer. Breast cancer tissues and adjacent tissues were obtained from 109 patients with breast cancer. The RNA extraction and quantification and immunohistochemical staining characterized the high expression of LINC00922 and low expression of NKD2 in breast cancer tissues in comparison to its adjacent counterparts. Furthermore, the ectopic expression and knockdown experiments were conducted to figure out the in vivo and in vitro effects of LINC00922 on breast cancer progression. The ectopically expressed LINC00922 activated the Wnt signaling pathway, promoted epithelial-mesenchymal transition, cell proliferative, invasive and migratory capacities, tumor growth and metastasis. Additionally, the RIP and ChIP assay identified that LINC00922 recruited DNMT1, DNMT3A and DNMT3B proteins in the promoter region of NKD2 to promote NKD2 promoter methylation, thus reducing the NKD2 expression. Moreover, the Wnt signaling pathway was activated subsequent to NKD2 silencing, which was reversed by LINC00922 silencing. Lastly, the anti-oncogenic effects of LINC00922 inhibition was antagonized after NKD2 knocked down. The current study provides evidence that LINC00922 acts as a tumor promoter by promoting NKD2 methylation. Hopefully, it provides a novel potential gene target for the treatment of breast cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2025

TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice.

Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.

Animals↗

PubMed2025

PRMT5 regulates alternative splicing of TCF3 under hypoxia to promote EMT and invasion in breast cancer.

Tumor hypoxia induced alterations in the epigenetic landscape and alternative splicing influence cellular adaptations. PRMT5 is a type II protein arginine methyltransferase that regulates several tumorigenic events in many cancer types. However, the regulation of PRMT5 and its direct implication on aberrant alternative splicing under hypoxia remains unexplored. In this study, we observed hypoxia-induced upregulation of PRMT5 via the CTCF in human breast cancer cells. Further, PRMT5-mediated symmetric arginine dimethylation H4R3me2s and H3R8me2s directly regulated the alternative splicing of TCF3. Under hypoxia, PRMT5-mediated histone dimethylation at the intronic conserved region (ICR) present between TCF3 exon 18a and exon 18b recruits DNMT3A, resulting in DNA methylation. DNA methylation at the TCF3-ICR is recognized and bound by MeCP2 resulting in RNA-Pol II pausing, promoting the recruitment of the negative splicing factor PTBP1 to the splicing locus of TCF3 pre-mRNA. PTBP1 promotes the exclusion of exon 18a which results in the production of the pro-invasive TCF3-18B (E47) isoform which promotes EMT and invasion of breast cancer cells under hypoxia. Collectively, our results indicate PRMT5-mediated symmetric arginine dimethylation of histones regulates alternative splicing of TCF3 gene thereby enhancing EMT and invasion in breast cancer hypoxia.

Humans↗