Validated Negative Regions (VNRs) in the VISTA Database Might Be Truncated Forms of Bona Fide Enhancers

Overview

Journal Adv Genet (Hoboken)

Specialty Genetics

Date 2024 Jun 17

PMID 38884049

Authors

Pengyu Ni

Siwen Wu

Zhengchang Su

Affiliations

Soon will be listed here.

Abstract

The VISTA enhancer database is a valuable resource for evaluating predicted enhancers in humans and mice. In addition to thousands of validated positive regions (VPRs) in the human and mouse genomes, the database also contains similar numbers of validated negative regions (VNRs). It is previously shown that the VPRs are on average half as long as predicted overlapping enhancers that are highly conserved and hypothesize that the VPRs may be truncated forms of long bona fide enhancers. Here, it is shown that like the VPRs, the VNRs also are under strong evolutionary constraints and overlap predicted enhancers in the genomes. The VNRs are also on average half as long as predicted overlapping enhancers that are highly conserved. Moreover, the VNRs and the VPRs display similar cell/tissue-specific modification patterns of key epigenetic marks of active enhancers. Furthermore, the VNRs and the VPRs show similar impact score spectra of in silico mutagenesis. These highly similar properties between the VPRs and the VNRs suggest that like the VPRs, the VNRs may also be truncated forms of long bona fide enhancers.

References

Peng T, Zhai Y, Atlasi Y, Ter Huurne M, Marks H, Stunnenberg H . STARR-seq identifies active, chromatin-masked, and dormant enhancers in pluripotent mouse embryonic stem cells. Genome Biol. 2020; 21(1):243. PMC: 7488044. DOI: 10.1186/s13059-020-02156-3. View

Pott S, Lieb J . What are super-enhancers?. Nat Genet. 2014; 47(1):8-12. DOI: 10.1038/ng.3167. View

Hoffman M, Buske O, Wang J, Weng Z, Bilmes J, Noble W . Unsupervised pattern discovery in human chromatin structure through genomic segmentation. Nat Methods. 2012; 9(5):473-6. PMC: 3340533. DOI: 10.1038/nmeth.1937. View

Ni P, Su Z . Accurate prediction of -regulatory modules reveals a prevalent regulatory genome of humans. NAR Genom Bioinform. 2021; 3(2):lqab052. PMC: 8210889. DOI: 10.1093/nargab/lqab052. View

Li Q, Peterson K, Fang X, Stamatoyannopoulos G . Locus control regions. Blood. 2002; 100(9):3077-86. PMC: 2811695. DOI: 10.1182/blood-2002-04-1104. View

Zhou J, Theesfeld C, Yao K, Chen K, Wong A, Troyanskaya O . Deep learning sequence-based ab initio prediction of variant effects on expression and disease risk. Nat Genet. 2018; 50(8):1171-1179. PMC: 6094955. DOI: 10.1038/s41588-018-0160-6. View

Visel A, Minovitsky S, Dubchak I, Pennacchio L . VISTA Enhancer Browser--a database of tissue-specific human enhancers. Nucleic Acids Res. 2006; 35(Database issue):D88-92. PMC: 1716724. DOI: 10.1093/nar/gkl822. View

Muerdter F, Boryn L, Woodfin A, Neumayr C, Rath M, Zabidi M . Resolving systematic errors in widely used enhancer activity assays in human cells. Nat Methods. 2017; 15(2):141-149. PMC: 5793997. DOI: 10.1038/nmeth.4534. View

Casper J, Zweig A, Villarreal C, Tyner C, Speir M, Rosenbloom K . The UCSC Genome Browser database: 2018 update. Nucleic Acids Res. 2017; 46(D1):D762-D769. PMC: 5753355. DOI: 10.1093/nar/gkx1020. View

10.

Ernst J, Kellis M . ChromHMM: automating chromatin-state discovery and characterization. Nat Methods. 2012; 9(3):215-6. PMC: 3577932. DOI: 10.1038/nmeth.1906. View

11.

Bradner J, Hnisz D, Young R . Transcriptional Addiction in Cancer. Cell. 2017; 168(4):629-643. PMC: 5308559. DOI: 10.1016/j.cell.2016.12.013. View

12.

Niu M, Tabari E, Ni P, Su Z . Towards a map of cis-regulatory sequences in the human genome. Nucleic Acids Res. 2018; 46(11):5395-5409. PMC: 6009671. DOI: 10.1093/nar/gky338. View

13.

Bai X, Shi S, Ai B, Jiang Y, Liu Y, Han X . ENdb: a manually curated database of experimentally supported enhancers for human and mouse. Nucleic Acids Res. 2019; 48(D1):D51-D57. PMC: 7145688. DOI: 10.1093/nar/gkz973. View

14.

Benton M, Talipineni S, Kostka D, Capra J . Genome-wide enhancer annotations differ significantly in genomic distribution, evolution, and function. BMC Genomics. 2019; 20(1):511. PMC: 6585034. DOI: 10.1186/s12864-019-5779-x. View

15.

Sant D, Sinclair M, Mungall C, Schulz S, Zerbino D, Lovering R . Sequence Ontology terminology for gene regulation. Biochim Biophys Acta Gene Regul Mech. 2021; 1864(10):194745. DOI: 10.1016/j.bbagrm.2021.194745. View

16.

Arnold C, Gerlach D, Stelzer C, Boryn L, Rath M, Stark A . Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science. 2013; 339(6123):1074-7. DOI: 10.1126/science.1232542. View

17.

Gorkin D, Barozzi I, Zhao Y, Zhang Y, Huang H, Lee A . An atlas of dynamic chromatin landscapes in mouse fetal development. Nature. 2020; 583(7818):744-751. PMC: 7398618. DOI: 10.1038/s41586-020-2093-3. View

18.

Ni P, Wu S, Su Z . Underlying causes for prevalent false positives and false negatives in STARR-seq data. NAR Genom Bioinform. 2023; 5(3):lqad085. PMC: 10516709. DOI: 10.1093/nargab/lqad085. View

19.

Batie M, Rocha S . Gene transcription and chromatin regulation in hypoxia. Biochem Soc Trans. 2020; 48(3):1121-1128. PMC: 7329336. DOI: 10.1042/BST20191106. View

20.

Gasperini M, Tome J, Shendure J . Towards a comprehensive catalogue of validated and target-linked human enhancers. Nat Rev Genet. 2020; 21(5):292-310. PMC: 7845138. DOI: 10.1038/s41576-019-0209-0. View