Promoter Shape Varies Across Populations and Affects Promoter Evolution and Expression Noise

Overview

Journal Nat Genet

Specialty Genetics

Date 2017 Feb 14

PMID 28191888

Citations 44

Authors

Ignacio E Schor

Jacob F Degner

Dermot Harnett

Enrico Cannavo

Francesco P Casale

Heejung Shim

David A Garfield

Ewan Birney

Matthew Stephens

Oliver Stegle

Eileen E M Furlong

Affiliations

Soon will be listed here.

Abstract

Animal promoters initiate transcription either at precise positions (narrow promoters) or dispersed regions (broad promoters), a distinction referred to as promoter shape. Although highly conserved, the functional properties of promoters with different shapes and the genetic basis of their evolution remain unclear. Here we used natural genetic variation across a panel of 81 Drosophila lines to measure changes in transcriptional start site (TSS) usage, identifying thousands of genetic variants affecting transcript levels (strength) or the distribution of TSSs within a promoter (shape). Our results identify promoter shape as a molecular trait that can evolve independently of promoter strength. Broad promoters typically harbor shape-associated variants, with signatures of adaptive selection. Single-cell measurements demonstrate that variants modulating promoter shape often increase expression noise, whereas heteroallelic interactions with other promoter variants alleviate these effects. These results uncover new functional properties of natural promoters and suggest the minimization of expression noise as an important factor in promoter evolution.

Citing Articles

A compendium of genetic variations associated with promoter usage across 49 human tissues.

Yuan J, Tong Y, Wang L, Yang X, Liu X, Shu M Nat Commun. 2024; 15(1):8758.

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Evidence for compensatory evolution within pleiotropic regulatory elements.

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Identifying promoter sequence architectures via a chunking-based algorithm using non-negative matrix factorisation.

Nikumbh S, Lenhard B PLoS Comput Biol. 2023; 19(11):e1011491.

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eRNA co-expression network uncovers TF dependency and convergent cooperativity.

Lee S, Kristjansdottir K, Kwak H Sci Rep. 2023; 13(1):19085.

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Plant Promoters and Terminators for High-Precision Bioengineering.

Brooks E, Elorriaga E, Liu Y, Duduit J, Yuan G, Tsai C Biodes Res. 2023; 5:0013.

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References

Merli C, Bergstrom D, Cygan J, Blackman R . Promoter specificity mediates the independent regulation of neighboring genes. Genes Dev. 1996; 10(10):1260-70. DOI: 10.1101/gad.10.10.1260. View

Arbiza L, Gronau I, Aksoy B, Hubisz M, Gulko B, Keinan A . Genome-wide inference of natural selection on human transcription factor binding sites. Nat Genet. 2013; 45(7):723-9. PMC: 3932982. DOI: 10.1038/ng.2658. View

Akalin A, Fredman D, Arner E, Dong X, Bryne J, Suzuki H . Transcriptional features of genomic regulatory blocks. Genome Biol. 2009; 10(4):R38. PMC: 2688929. DOI: 10.1186/gb-2009-10-4-r38. View

Sandelin A, Carninci P, Lenhard B, Ponjavic J, Hayashizaki Y, Hume D . Mammalian RNA polymerase II core promoters: insights from genome-wide studies. Nat Rev Genet. 2007; 8(6):424-36. DOI: 10.1038/nrg2026. View

Mackay T, Richards S, Stone E, Barbadilla A, Ayroles J, Zhu D . The Drosophila melanogaster Genetic Reference Panel. Nature. 2012; 482(7384):173-8. PMC: 3683990. DOI: 10.1038/nature10811. View

Zehavi Y, Kuznetsov O, Ovadia-Shochat A, Juven-Gershon T . Core promoter functions in the regulation of gene expression of Drosophila dorsal target genes. J Biol Chem. 2014; 289(17):11993-12004. PMC: 4002106. DOI: 10.1074/jbc.M114.550251. View

Cannavo E, Koelling N, Harnett D, Garfield D, Casale F, Ciglar L . Genetic variants regulating expression levels and isoform diversity during embryogenesis. Nature. 2016; 541(7637):402-406. DOI: 10.1038/nature20802. View

Xi L, Fondufe-Mittendorf Y, Xia L, Flatow J, Widom J, Wang J . Predicting nucleosome positioning using a duration Hidden Markov Model. BMC Bioinformatics. 2010; 11:346. PMC: 2900280. DOI: 10.1186/1471-2105-11-346. View

Ohler U . Identification of core promoter modules in Drosophila and their application in accurate transcription start site prediction. Nucleic Acids Res. 2006; 34(20):5943-50. PMC: 1635271. DOI: 10.1093/nar/gkl608. View

10.

Forrest A, Kawaji H, Rehli M, Baillie J, de Hoon M, Haberle V . A promoter-level mammalian expression atlas. Nature. 2014; 507(7493):462-70. PMC: 4529748. DOI: 10.1038/nature13182. View

11.

Gronau I, Arbiza L, Mohammed J, Siepel A . Inference of natural selection from interspersed genomic elements based on polymorphism and divergence. Mol Biol Evol. 2013; 30(5):1159-71. PMC: 3697874. DOI: 10.1093/molbev/mst019. View

12.

Dreos R, Ambrosini G, Bucher P . Influence of Rotational Nucleosome Positioning on Transcription Start Site Selection in Animal Promoters. PLoS Comput Biol. 2016; 12(10):e1005144. PMC: 5055345. DOI: 10.1371/journal.pcbi.1005144. View

13.

Massouras A, Waszak S, Albarca-Aguilera M, Hens K, Holcombe W, Ayroles J . Genomic variation and its impact on gene expression in Drosophila melanogaster. PLoS Genet. 2012; 8(11):e1003055. PMC: 3499359. DOI: 10.1371/journal.pgen.1003055. View

14.

Nozaki T, Yachie N, Ogawa R, Kratz A, Saito R, Tomita M . Tight associations between transcription promoter type and epigenetic variation in histone positioning and modification. BMC Genomics. 2011; 12:416. PMC: 3170308. DOI: 10.1186/1471-2164-12-416. View

15.

Lappalainen T, Sammeth M, Friedlander M, t Hoen P, Monlong J, Rivas M . Transcriptome and genome sequencing uncovers functional variation in humans. Nature. 2013; 501(7468):506-11. PMC: 3918453. DOI: 10.1038/nature12531. View

16.

Francesconi M, Lehner B . The effects of genetic variation on gene expression dynamics during development. Nature. 2013; 505(7482):208-11. DOI: 10.1038/nature12772. View

17.

Li X, Noll M . Compatibility between enhancers and promoters determines the transcriptional specificity of gooseberry and gooseberry neuro in the Drosophila embryo. EMBO J. 1994; 13(2):400-6. PMC: 394821. DOI: 10.1002/j.1460-2075.1994.tb06274.x. View

18.

FitzGerald P, Sturgill D, Shyakhtenko A, Oliver B, Vinson C . Comparative genomics of Drosophila and human core promoters. Genome Biol. 2006; 7(7):R53. PMC: 1779564. DOI: 10.1186/gb-2006-7-7-r53. View

19.

Gaffney D, Veyrieras J, Degner J, Pique-Regi R, Pai A, Crawford G . Dissecting the regulatory architecture of gene expression QTLs. Genome Biol. 2012; 13(1):R7. PMC: 3334587. DOI: 10.1186/gb-2012-13-1-r7. View

20.

Lenhard B, Sandelin A, Carninci P . Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nat Rev Genet. 2012; 13(4):233-45. DOI: 10.1038/nrg3163. View