Sangam: A Confluence of Knowledge Streams

Compatibility rules of human enhancer and promoter sequences

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dc.creator Bergman, Drew T
dc.creator Jones, Thouis R
dc.creator Liu, Vincent
dc.creator Ray, Judhajeet
dc.creator Jagoda, Evelyn
dc.creator Siraj, Layla
dc.creator Kang, Helen Y
dc.creator Nasser, Joseph
dc.creator Kane, Michael
dc.creator Rios, Antonio
dc.creator Nguyen, Tung H
dc.creator Grossman, Sharon R
dc.creator Fulco, Charles P
dc.creator Lander, Eric S
dc.creator Engreitz, Jesse M
dc.date 2023-01-10T17:57:19Z
dc.date 2023-01-10T17:57:19Z
dc.date 2022
dc.date 2023-01-10T17:50:10Z
dc.date.accessioned 2023-02-17T20:15:05Z
dc.date.available 2023-02-17T20:15:05Z
dc.identifier https://hdl.handle.net/1721.1/147044
dc.identifier Bergman, Drew T, Jones, Thouis R, Liu, Vincent, Ray, Judhajeet, Jagoda, Evelyn et al. 2022. "Compatibility rules of human enhancer and promoter sequences." Nature, 607 (7917).
dc.identifier.uri http://localhost:8080/xmlui/handle/CUHPOERS/242337
dc.description Gene regulation in the human genome is controlled by distal enhancers that activate specific nearby promoters1. A proposed model for this specificity is that promoters have sequence-encoded preferences for certain enhancers, for example, mediated by interacting sets of transcription factors or cofactors2. This 'biochemical compatibility' model has been supported by observations at individual human promoters and by genome-wide measurements in Drosophila3-9. However, the degree to which human enhancers and promoters are intrinsically compatible has not yet been systematically measured, and how their activities combine to control RNA expression remains unclear. Here we design a high-throughput reporter assay called enhancer × promoter self-transcribing active regulatory region sequencing (ExP STARR-seq) and applied it to examine the combinatorial compatibilities of 1,000 enhancer and 1,000 promoter sequences in human K562 cells. We identify simple rules for enhancer-promoter compatibility, whereby most enhancers activate all promoters by similar amounts, and intrinsic enhancer and promoter activities multiplicatively combine to determine RNA output (R2 = 0.82). In addition, two classes of enhancers and promoters show subtle preferential effects. Promoters of housekeeping genes contain built-in activating motifs for factors such as GABPA and YY1, which decrease the responsiveness of promoters to distal enhancers. Promoters of variably expressed genes lack these motifs and show stronger responsiveness to enhancers. Together, this systematic assessment of enhancer-promoter compatibility suggests a multiplicative model tuned by enhancer and promoter class to control gene transcription in the human genome.
dc.format application/pdf
dc.language en
dc.publisher Springer Science and Business Media LLC
dc.relation 10.1038/S41586-022-04877-W
dc.relation Nature
dc.rights Creative Commons Attribution-Noncommercial-Share Alike
dc.rights http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.source PMC
dc.title Compatibility rules of human enhancer and promoter sequences
dc.type Article
dc.type http://purl.org/eprint/type/JournalArticle


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