Transcription Imparts Architecture, Function and Logic to Enhancer Units

Overview

Journal Nat Genet

Specialty Genetics

Date 2020 Sep 22

PMID 32958950

Citations 41

Authors

Nathaniel D Tippens

Jin Liang

Alden King-Yung Leung

Shayne D Wierbowski

Abdullah Ozer

James G Booth

John T Lis

Haiyuan Yu

Affiliations

Soon will be listed here.

Abstract

Distal enhancers play pivotal roles in development and disease yet remain one of the least understood regulatory elements. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites are robust predictors of active enhancers with higher resolution than histone modifications. We show that active enhancer units are precisely delineated by active transcription start sites, validate that these boundaries are sufficient for capturing enhancer function, and confirm that core promoter sequences are necessary for this activity. We assay adjacent enhancers and find that their joint activity is often driven by the stronger unit within the cluster. Finally, we validate these results through functional dissection of a distal enhancer cluster using CRISPR-Cas9 deletions. In summary, definition of high-resolution enhancer boundaries enables deconvolution of complex regulatory loci into modular units.

Citing Articles

Cell type-dependent directional transcription at enhancers.

Agrawal S, Kanamaru E, Saito Y, Ishikawa F, de Hoon M NAR Genom Bioinform. 2025; 7(1):lqaf007.

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Systematic functional characterization of non-coding regulatory SNPs associated with central obesity.

Dong S, Duan Y, Zhu R, Jia Y, Chen J, Huang X Am J Hum Genet. 2025; 112(1):116-134.

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Training deep learning models on personalized genomic sequences improves variant effect prediction.

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Position-dependent function of human sequence-specific transcription factors.

Duttke S, Guzman C, Chang M, Delos Santos N, McDonald B, Xie J Nature. 2024; 631(8022):891-898.

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Single-cell nascent RNA sequencing unveils coordinated global transcription.

Mahat D, Tippens N, Martin-Rufino J, Waterton S, Fu J, Blatt S Nature. 2024; 631(8019):216-223.

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