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

Ravi V. Desai, Xinyue Chen, Benjamin Martin, Sonali Chaturvedi, Dong Woo Hwang, Weihan Li, Chen Yu, Sheng Ding, Matt Thomson, Robert H. Singer, Robert A. Coleman, Maike M.K. Hansen, Leor S. Weinberger

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number870
JournalScience
Volume373
Issue number6557
DOIs
StatePublished - Aug 20 2021

ASJC Scopus subject areas

  • General

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