Discovery of an endogenous cellular pathway that regulates transcriptional noise to promote cell-fate specificationLeor WeinbergerUniv. of California San Francisco (UCSF); Gladstone Institutes

Stochastic fluctuations in gene expression (‘noise’) are often considered detrimental but, in other fields, fluctuations are harnessed for benefit (e.g., ‘dither’ or amplification of thermal fluctuations to accelerate chemical reactions). We recently showed that DNA base-excision repair amplifies transcriptional noise to generate increased cellular plasticity and facilitate cellular reprogramming (Desai et al. Science 2021). 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. Strikingly, this homeostatic noise amplification mechanism, termed ‘Discordant Transcription through Repair’ (DiThR; pronounced /’dither’/), potentiates cellular reprogramming and differentiation. These data reveal a functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.