Molecular mechanisms of promoter silencing by transcriptional readthrough.

Transcriptional readthrough induces stable gene silencing through a hierarchical cascade involving antisense transcription, H3K36me3 deposition, and DNA methylation in mouse cells.

• Why it matters: Understanding how transcriptional interference leads to long-term gene repression is crucial for insights into epigenetic regulation and disease mechanisms, such as cobalamin C deficiency.
• What they did: The study developed a mouse cell model with antisense transcription across Mmachc, and systematically perturbed transcription and chromatin-modifying machinery to analyze silencing mechanisms, focusing on H3K36me3 and DNA methylation.
• The result: Antisense transcription was identified as the main driver of repression, with H3K36me3 directly contributing to silencing and necessary for DNA methylation establishment, which confers long-term gene repression.