Epigenetic reprogramming of terminal T cell differentiation via DNMT1 inhibition reverses terminal DNA methylation and enhances multipotency 2259880

Decoding Histone-DNA Methylation Crosstalk in Exhausted T Cells to Enhance Immunotherapy 2253691

A central histone—DNA methylation circuit, regulated by KDM5A/B and DNMT3A, that drives epigenetic scarring and terminal exhaustion in CD8 T cells is uncovered and Therapeutic targeting of this circuit offers a novel approach to epigenetically reprogram TEX cells and enhance the efficacy of cancer immunotherapy.

Epigenetic Reactivation of Lineage Differentiation to Target Leukemia

Epigenetic mechanisms controlling longevity of T cell immunity 2259637

Long-lived T cell immunity can protect against endemic pathogens that result in iterative challenge to the host, but how such repeated activation of T cells impacts on the molecular mechanisms governing memory potential remains largely unclear. Here, we assessed the role of de novo epigenetic programs in shaping the repertoire and recall response of memory T cells in a setting of iterative acute viral infection. Using our previously established CRISPR system for deleting epigenetic regulators (Kang et al, 2024, Science), we optimized an iterative acute viral infection model with LCMV to serially activate Dnmt3a deficient memory T cells. CRISPR-edited Dnmt3a-deficient P14 CD8 T cells were adoptively transferred cells into B6 mice and subjected to acute infections. Based on our previously established acute viral infection, we evaluated the impact of repetitive antigen exposure on memory CD8 T cells differentiation, longevity, proliferation, cytotoxicity and anti-tumor activity. Dnmt3a KO retain potentially memory CD8 T cells stronger proliferative capacity during acutely prolonged stimulation, but non-target sgRNA group P14 ratio gradually decrease. Additionally, Dnmt3a knockout T cells displayed sustained memory precursor features, including higher CXCR3, Ly108, and TCF1, with lower PD-1 and Tim-3 expression. Functionally, they produced more IL-2, suggesting enhanced viral clearance and overall T cell survival. These results indicate that loss of Dnmt3a preserves stem-like properties and enhance the long-term persistence of memory CD8 T cells under repetitive antigen exposure, providing an epigenetic mechanism to improve immune durability. Our findings show that Dnmt3a KO T cells have increased T cell stemness and durability and indicate that Dnmt3a drives CD8 T cell memory capacity during iterative acute stimulation. These results clarify our research direction that de novo epigenetic programming continues to shape T cell repertoire and recall memory response. National Institutes of Health Immune Response Regulation: Molecular Mechanisms (IRM)

Targeting DNA Methylation: New Paradigms and the Advent of Gene-Selective Tools.

The mechanisms and roles of DNA methylation in epigenetic regulation are examined, the current landscape of DNA methylation modulators are evaluated, from traditional DNMT inhibitors to cutting-edge CRISPR-dCas9 fusion systems and protein-protein interaction disruptors, and their clinical relevance are evaluated.

Interplay Between DNA and RNA Methylation Shapes Cancer Cell Plasticity.

Cellular plasticity refers to the ability of healthy cells to shift between phenotypic states and modify their characteristics to maintain tissue homeostasis and integrity. In the tumor context, cancer stem cells (CSCs) exploit this flexibility to withstand stress, facilitate tumor dissemination, and evade therapeutic interventions. Epigenetic regulation, particularly DNA methylation at CpG sites, is recognized as a well-known driver of tumor plasticity by repressing differentiation programs through modulation of chromatin accessibility. More recently, RNA modifications (epitranscriptomics) have emerged as crucial post-transcriptional regulators of gene expression that shape RNA fate and function. Among these, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G) contribute to the regulation of cell identity by modulating stemness-differentiation balance, stress adaptation, and epithelial-to-mesenchymal transition (EMT). Notably, dysregulation of both DNA and RNA methylation signatures is frequently observed in tumors, suggesting potential functional interactions between these regulatory layers. Emerging evidence indicates that DNA CpG methylation and RNA methylation pathways may cooperate to influence stemness, survival, and EMT-associated signaling, thereby supporting CSCs' plasticity. Although the molecular mechanisms underlying this crosstalk remain incompletely understood, accumulating studies suggest that DNA and RNA methylation could converge within interconnected regulatory networks that contribute to the control of cancer cell identity. A deeper understanding of these interactions may uncover novel vulnerabilities for targeting tumor plasticity. In this review, we summarize the current knowledge on the interplay between DNA and RNA methylation in regulating tumor plasticity, highlighting emerging mechanistic insights, functional interactions, and potential implications for future epigenetic and epitranscriptomic therapeutic strategies.

Epigenetic priming and locus-specific demethylation enhance cell-death susceptibility in liver cancer.

Results indicate that targeted reactivation of BFL-1 and SQOR increases cell-death susceptibility in liver cancer cells, providing proof-of-concept for locus-specific epigenetic therapy in liver cancer.