1. A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions
- Author
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Desai, Ravi V, Chen, Xinyue, Martin, Benjamin, Chaturvedi, Sonali, Hwang, Dong Woo, Li, Weihan, Yu, Chen, Ding, Sheng, Thomson, Matt, Singer, Robert H, Coleman, Robert A, Hansen, Maike MK, and Weinberger, Leor S
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Genetics ,Clinical Sciences ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Animals ,Cell Differentiation ,Cells ,Cultured ,Cellular Reprogramming ,Computer Simulation ,DNA ,DNA Repair ,DNA-(Apurinic or Apyrimidinic Site) Lyase ,Embryonic Stem Cells ,Gene Expression ,Idoxuridine ,Mice ,Models ,Genetic ,Nanog Homeobox Protein ,Nucleic Acid Conformation ,RNA ,Messenger ,Single-Cell Analysis ,Stochastic Processes ,Thymidine Kinase ,Transcription ,Genetic ,General Science & Technology - Abstract
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.
- Published
- 2021