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

Desai, Ravi V. and Chen, Xinyue and Martin, Benjamin and Chaturvedi, Sonali and Hwang, Dong Woo and Li, Weihan and Yu, Chen and Ding, Sheng and Thomson, Matt and Singer, Robert H. and Coleman, Robert A. and Hansen, Maike M. K. and Weinberger, Leor S. (2021) A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions. Science, 373 (6557). Art. No. eabc6506. ISSN 0036-8075. PMCID PMC8667278. doi:10.1126/science.abc6506. https://resolver.caltech.edu/CaltechAUTHORS:20210726-193944737

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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.

Item Type:

Article

Related URLs:

URL	URL Type	Description
https://doi.org/10.1126/science.abc6506	DOI	Article
https://science.sciencemag.org/content/suppl/2021/07/21/science.abc6506.DC1	Publisher	Supplementary Materials
https://github.com/weinbergerlab-ucsf/Code_Desai_et_al	Related Item	Code
https://doi.org/10.5281/zenodo.4891977	DOI	Code

ORCID:

Author	ORCID
Desai, Ravi V.	0000-0002-0336-0883
Chen, Xinyue	0000-0001-8288-7685
Martin, Benjamin	0000-0002-9673-2008
Chaturvedi, Sonali	0000-0002-9175-8110
Hwang, Dong Woo	0000-0001-5806-067X
Li, Weihan	0000-0003-4718-1884
Ding, Sheng	0000-0002-7525-2144
Thomson, Matt	0000-0003-1021-1234
Hansen, Maike M. K.	0000-0001-7998-6631
Weinberger, Leor S.	0000-0002-9987-6357

Additional Information:

© 2021 American Association for the Advancement of Science. This is an article distributed under the terms of the Science Journals Default License. 31 May 2020; accepted 8 July 2021; Published online 22 July 2021. We thank M. Simpson, B. Bruneau, J. Weissman, G. Balazsi, and members of the Weinberger laboratory for thoughtful discussions and suggestions; K. Claiborn for editing; G. Maki for graphics support; N. Raman in the Gladstone Institute Flow Cytometry Facility (NIH S10 RR028962, P30 AI027763, DARPA, and the James B. Pendleton Charitable Trust) for technical assistance; the Gladstone Assay Development and Drug Discovery Core for technical assistance with drug screening; K. Thorn and D. Larson in the UCSF Nikon Imaging Center (NIH S10 1S10OD017993-01A1) for technical assistance with imaging; M. Jost and J. Weissman for CRISPRi reagents; and the Gladstone Institute Genomics Core for technical assistance with single-cell RNA-sequencing. The dual-tagged Sox2 mESCs were a kind donation from B. Bruneau and E. Nora. The Oct4-GFP reprogrammable MEFs (harbor stably integrated OKSM factors) were a kind donation from S. Guo. R.V.D. is supported by an NIH/NICHD F30 fellowship (HD095614-03). R.A.C. acknowledges support from NIH award 1R01GM126045-05. R.H.S. acknowledges support from NIH awards NS083085 and 1R35GM136296. M.M.K.H. acknowledges support from a Dutch Research Council (NWO) ENW-XS award (OCENW.XS3.055). L.S.W. acknowledges support from a Bowes Distinguished Professorship, Alfred P. Sloan Research Fellowship, Pew Scholars in the Biomedical Sciences Program, NIH award R01AI109593, and the NIH Director’s New Innovator Award (OD006677) and Pioneer Award (OD17181) programs. Author contributions: R.V.D., M.T., and L.S.W. conceived and designed the study. R.V.D., B.M., and M.T. analyzed the sequencing data. R.V.D., X.C., C.U., S.D., and L.S.W conceived and designed the cellular reprogramming experiments. X.C., D.W.H., W.L., R.H.S., R.A.C., and L.S.W conceived and designed the MS2 imaging experiments. R.V.D., X.C., S.C., D.W.H., W.L., and C.U. performed the experiments. R.V.D., X.C., B.M., M.T., R.A.C., M.M.K.H., and L.S.W. analyzed data. R.V.D., M.M.K.H., B.M., and L.S.W. constructed and analyzed the mathematical models. R.V.D., M.M.K.H., and L.S.W. wrote the manuscript. The authors declare no competing interests. Data and materials availability: The raw and processed sequencing data reported herein have been deposited onto the Gene Expression Omnibus under accession number GSE176044. Custom code for analysis of scRNA-seq data and mathematical modeling are available on GitHub at https://github.com/weinbergerlab-ucsf/Code_Desai_et_al and are archived on Zenodo (79). Reagents, including plasmids and cell lines, are available from the corresponding author upon request.

Funders:

Funding Agency	Grant Number
NIH Postdoctoral Fellowship	F30HD095614-03
NIH	1R01GM126045-05
NIH	NS083085
NIH	1R35GM136296
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)	OCENW.XS3.055
Bowes Distinguished Professorship	UNSPECIFIED
Alfred P. Sloan Foundation	UNSPECIFIED
Pew Charitable Trust	UNSPECIFIED
NIH	R01AI109593
NIH	OD006677
NIH	OD17181

Issue or Number:

6557

PubMed Central ID:

PMC8667278

DOI:

10.1126/science.abc6506

Record Number:

CaltechAUTHORS:20210726-193944737

Persistent URL:

https://resolver.caltech.edu/CaltechAUTHORS:20210726-193944737

Official Citation:

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 and Leor S. Weinberger. Science 373 (6557), eabc6506; DOI: 10.1126/science.abc6506

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No commercial reproduction, distribution, display or performance rights in this work are provided.

ID Code:

110014

Collection:

CaltechAUTHORS

Deposited By:

Tony Diaz

Deposited On:

26 Jul 2021 22:27

Last Modified:

25 Jan 2022 16:54

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