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Genome-wide analysis of CRISPR perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions

A single gene may be regulated by multiple enhancers, but how they work in concert to regulate transcription is poorly understood. Prior studies have mostly examined enhancers at single loci and have reached inconsistent conclusions about whether epistatic-like interactions exist between them. To an...

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Autores principales: Zhou, Jessica, Guruvayurappan, Karthik, Chen, Hsiuyi V., Chen, Aaron R., McVicker, Graham
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10168320/
https://www.ncbi.nlm.nih.gov/pubmed/37163096
http://dx.doi.org/10.1101/2023.04.26.538501
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author Zhou, Jessica
Guruvayurappan, Karthik
Chen, Hsiuyi V.
Chen, Aaron R.
McVicker, Graham
author_facet Zhou, Jessica
Guruvayurappan, Karthik
Chen, Hsiuyi V.
Chen, Aaron R.
McVicker, Graham
author_sort Zhou, Jessica
collection PubMed
description A single gene may be regulated by multiple enhancers, but how they work in concert to regulate transcription is poorly understood. Prior studies have mostly examined enhancers at single loci and have reached inconsistent conclusions about whether epistatic-like interactions exist between them. To analyze enhancer interactions throughout the genome, we developed a statistical framework for CRISPR regulatory screens that utilizes negative binomial generalized linear models that account for variable guide RNA (gRNA) efficiency. We reanalyzed a single-cell CRISPR interference experiment that delivered random combinations of enhancer-targeting gRNAs to each cell and interrogated interactions between 3,808 enhancer pairs. We found that enhancers act multiplicatively with one another to control gene expression, but our analysis provides no evidence for interaction effects between pairs of enhancers regulating the same gene. Our findings illuminate the regulatory behavior of multiple enhancers and our statistical framework provides utility for future analyses studying interactions between enhancers.
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spelling pubmed-101683202023-05-10 Genome-wide analysis of CRISPR perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions Zhou, Jessica Guruvayurappan, Karthik Chen, Hsiuyi V. Chen, Aaron R. McVicker, Graham bioRxiv Article A single gene may be regulated by multiple enhancers, but how they work in concert to regulate transcription is poorly understood. Prior studies have mostly examined enhancers at single loci and have reached inconsistent conclusions about whether epistatic-like interactions exist between them. To analyze enhancer interactions throughout the genome, we developed a statistical framework for CRISPR regulatory screens that utilizes negative binomial generalized linear models that account for variable guide RNA (gRNA) efficiency. We reanalyzed a single-cell CRISPR interference experiment that delivered random combinations of enhancer-targeting gRNAs to each cell and interrogated interactions between 3,808 enhancer pairs. We found that enhancers act multiplicatively with one another to control gene expression, but our analysis provides no evidence for interaction effects between pairs of enhancers regulating the same gene. Our findings illuminate the regulatory behavior of multiple enhancers and our statistical framework provides utility for future analyses studying interactions between enhancers. Cold Spring Harbor Laboratory 2023-04-27 /pmc/articles/PMC10168320/ /pubmed/37163096 http://dx.doi.org/10.1101/2023.04.26.538501 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Zhou, Jessica
Guruvayurappan, Karthik
Chen, Hsiuyi V.
Chen, Aaron R.
McVicker, Graham
Genome-wide analysis of CRISPR perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions
title Genome-wide analysis of CRISPR perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions
title_full Genome-wide analysis of CRISPR perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions
title_fullStr Genome-wide analysis of CRISPR perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions
title_full_unstemmed Genome-wide analysis of CRISPR perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions
title_short Genome-wide analysis of CRISPR perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions
title_sort genome-wide analysis of crispr perturbations indicates that enhancers act multiplicatively and without epistatic-like interactions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10168320/
https://www.ncbi.nlm.nih.gov/pubmed/37163096
http://dx.doi.org/10.1101/2023.04.26.538501
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