Compatibility rules of human enhancer and promoter sequences

Bergman, Drew T.; Jones, Thouis R.; Liu, Vincent; Ray, Judhajeet; Jagoda, Evelyn; Siraj, Layla; Kang, Helen Y.; Nasser, Joseph; Kane, Michael F.; Rios, Antonio Ray; Nguyen, Tung H.; Grossman, Sharon R.; Fulco, Charles P.; Lander, Eric S.; Engreitz, Jesse M.

doi:10.1038/s41586-022-04877-w

Cited by 84 publications

(100 citation statements)

References 63 publications

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“…An MPRA study in Drosophila cells using seven different promoters and genome-wide cCREs suggested that cCRE-P specificity broadly separates between housekeeping and tissue-specific promoters (Zabidi et al, 2015). Parallel to our work, a MPRA study was reported of thousands of cCRE-P combinations in a human cell line (Bergman et al, 2022).…”

Section: Discussionsupporting

confidence: 71%

“…By statistical analysis, we found that more than half of the cCREs exhibit a degree of specificity that cannot be explained by experimental noise. We also found evidence for such specificity in the MPRA data of Bergman et al (2022). Although this study focused on the observation that a substantial fraction of the variance in reporter activity can be explained by a multiplicative combination of enhancer and promoter activities, both datasets indicate that CRE-P selectivity as well as intrinsic enhancer and promoter activities contribute to reporter expression (see also Bergman et al [2022]).…”

Section: Discussionmentioning

confidence: 66%

“…We also found evidence for such specificity in the MPRA data of Bergman et al (2022). Although this study focused on the observation that a substantial fraction of the variance in reporter activity can be explained by a multiplicative combination of enhancer and promoter activities, both datasets indicate that CRE-P selectivity as well as intrinsic enhancer and promoter activities contribute to reporter expression (see also Bergman et al [2022]). We suggest that such a general multiplicative rule and a more complex grammar of enhancer-promoter specificities are two sides of the same coin of gene regulation.…”

Section: Discussionmentioning

confidence: 66%

“…In a parallel study, Bergman et al (2022) conducted similar largescale cCRE-P combinatorial MPRAs in human K562 cells. Based on mathematical modeling of their data, the authors proposed that intrinsic cCRE and P activities generally combine multiplicatively to determine reporter activity.…”

Section: Similar Results With An Independent Mpra Dataset From Human ...mentioning

confidence: 99%

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Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome

et al. 2022

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 66%

Section: Similar Results With An Independent Mpra Dataset From Human ...mentioning

confidence: 99%

See 2 more Smart Citations

Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome

et al. 2022

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“…enhancer adoption/hijacking) (Lupiáñez et al, 2015), or by the duplication of enhancers (Lohan et al, 2014). Nevertheless, predicting the pathological consequences of TAD disruption is complicated by the fact that, besides TAD organization, other genetic and epigenetic features also contribute to productive gene-enhancer communication (Ghavi-Helm, 2019; Sánchez-Gaya et al, 2020; Pachano et al, 2021; Batut et al, 2022; Bergman et al, 2022; Zuin et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

POSTRE: a tool to predict the pathological effects of human structural variants

Sánchez-Gaya

Rada-Iglesias

2022

Preprint

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Understanding the pathological impact of non-coding genetic variation is a major challenge in medical genetics. Accumulating evidences indicate that a significant fraction of genetic alterations, including structural variants (SVs), can cause human disease by altering the function of non-coding regulatory elements, such as enhancers. In the case of SVs, described pathomechanisms include changes in enhancer dosage and long-range enhancer-gene communication. However, there is still a clear gap between the need to predict and interpret the medical impact of non-coding variants, and the existence of tools to properly perform these tasks. To reduce this gap, we have developed POSTRE (Prediction Of STRuctural variant Effects), a computational tool to predict the pathogenicity of SVs implicated in a broad range of human congenital disorders. By considering disease-relevant cellular contexts, POSTRE identifies SVs with either coding or long range pathological consequences with high specificity and sensitivity. Furthermore, POSTRE not only identifies pathogenic SVs, but also predicts the disease-causative genes and the underlying pathological mechanism (e.g, gene deletion, enhancer disconnection, enhancer adoption, etc.). POSTRE is available at https://github.com/vicsanga/Postre.

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What is an enhancer?

Thomas

Buecker

2023

BioEssays

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Tight control of the transcription process is essential for the correct spatial and temporal gene expression pattern during development and in homeostasis. Enhancers are at the core of correct transcriptional activation. The original definition of an enhancer is straightforward: a DNA sequence that activates transcription independent of orientation and direction. Dissection of numerous enhancer loci has shown that many enhancer‐like elements might not conform to the original definition, suggesting that enhancers and enhancer‐like elements might use multiple different mechanisms to contribute to transcriptional activation. Here, we review methodologies to identify enhancers and enhancer‐like elements and discuss pitfalls and consequences for our understanding of transcriptional regulation.

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Compatibility rules of human enhancer and promoter sequences

Cited by 84 publications

References 63 publications

Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome

Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome

POSTRE: a tool to predict the pathological effects of human structural variants

What is an enhancer?

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