Stochastic fluctuations in gene expression (“noise”) are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as “discordant transcription through repair” (“DiThR,” which is pronounced “dither”), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.

基因表达的随机波动（“噪音”）通常被认为是有害的，但也可以利用波动来获取利益（例如，抖动）。我们在这里展示了 DNA 碱基切除修复放大了转录噪声以促进细胞重编程。具体来说，识别自然发生和非自然碱基修饰的 DNA 修复蛋白 Apex1 会放大表达噪音，同时保持平均表达水平。这种放大的表达噪音源于由 Apex1 介导的 DNA 超螺旋产生的持续时间较短、强度较高的转录爆发。DNA 拓扑结构的重塑首先阻碍然后加速转录以维持平均水平。这种机制，我们称之为“通过修复的不一致转录”（“DiThR”，发音为“dither”），增强细胞重编程和分化。我们的研究揭示了由 DNA 碱基修饰介导的转录波动在胚胎发育和疾病中的潜在功能作用。