A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions

Science. 2021 Aug 20;373(6557):eabc6506. doi: 10.1126/science.abc6506. Epub 2021 Jul 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cells, Cultured
  • Cellular Reprogramming*
  • Computer Simulation
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • DNA Repair*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism*
  • Embryonic Stem Cells
  • Gene Expression* / drug effects
  • Idoxuridine / metabolism
  • Idoxuridine / pharmacology
  • Mice
  • Models, Genetic
  • Nanog Homeobox Protein / genetics
  • Nucleic Acid Conformation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Single-Cell Analysis
  • Stochastic Processes
  • Thymidine Kinase / genetics
  • Thymidine Kinase / metabolism
  • Transcription, Genetic* / drug effects


  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • RNA, Messenger
  • DNA
  • Thymidine Kinase
  • thymidine kinase 1
  • Apex1 protein, mouse
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • Idoxuridine