1. A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions.
- Author
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Desai RV, Chen X, Martin B, Chaturvedi S, Hwang DW, Li W, Yu C, Ding S, Thomson M, Singer RH, Coleman RA, Hansen MMK, and Weinberger LS
- Subjects
- Animals, Cells, Cultured, Computer Simulation, DNA genetics, DNA metabolism, Embryonic Stem Cells, 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, Cell Differentiation, Cellular Reprogramming, DNA chemistry, DNA Repair, DNA-(Apurinic or Apyrimidinic Site) Lyase metabolism, Gene Expression drug effects, Transcription, Genetic drug effects
- 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., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2021
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