Epigenomic circuits shaping cellular heterogeneity in pleural mesothelioma

Single-cell chromatin accessibility and matched transcriptomics in pleural mesothelioma identify NR4A2-linked regulatory circuitry, including a state-specific distal enhancer, validated in Jurkat cells.

• Why it matters: Pleural mesothelioma remains lethal with limited treatment benefit, and the field lacks epigenomic explanations for the cellular heterogeneity that may shape tumor progression and immune dysfunction.
• What they did: The study profiled patient-matched samples using single-cell chromatin accessibility and transcriptomics, then tested transcriptional regulators via genetic perturbations across four PM cell lines. It also compared exhausted CD8 T and KLRC1 natural killer cell chromatin landscapes and experimentally validated enhancer control of NR4A2 expression in Jurkat cells.
• The result: The work provides an epigenomic map of PM and nominates candidate transcription factors and regulatory elements, including NR4A2 and its enhancer, for future functional studies and potential epigenetic editing strategies.

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