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Computational identification and experimental characterization of preferred downstream positions in human core promoters.

Authors :
René Dreos
Anna Sloutskin
Nati Malachi
Diana Ideses
Philipp Bucher
Tamar Juven-Gershon
Source :
PLoS Computational Biology, Vol 17, Iss 8, p e1009256 (2021)
Publication Year :
2021
Publisher :
Public Library of Science (PLoS), 2021.

Abstract

Metazoan core promoters, which direct the initiation of transcription by RNA polymerase II (Pol II), may contain short sequence motifs termed core promoter elements/motifs (e.g. the TATA box, initiator (Inr) and downstream core promoter element (DPE)), which recruit Pol II via the general transcription machinery. The DPE was discovered and extensively characterized in Drosophila, where it is strictly dependent on both the presence of an Inr and the precise spacing from it. Since the Drosophila DPE is recognized by the human transcription machinery, it is most likely that some human promoters contain a downstream element that is similar, though not necessarily identical, to the Drosophila DPE. However, only a couple of human promoters were shown to contain a functional DPE, and attempts to computationally detect human DPE-containing promoters have mostly been unsuccessful. Using a newly-designed motif discovery strategy based on Expectation-Maximization probabilistic partitioning algorithms, we discovered preferred downstream positions (PDP) in human promoters that resemble the Drosophila DPE. Available chromatin accessibility footprints revealed that Drosophila and human Inr+DPE promoter classes are not only highly structured, but also similar to each other, particularly in the proximal downstream region. Clustering of the corresponding sequence motifs using a neighbor-joining algorithm strongly suggests that canonical Inr+DPE promoters could be common to metazoan species. Using reporter assays we demonstrate the contribution of the identified downstream positions to the function of multiple human promoters. Furthermore, we show that alteration of the spacing between the Inr and PDP by two nucleotides results in reduced promoter activity, suggesting a spacing dependency of the newly discovered human PDP on the Inr. Taken together, our strategy identified novel functional downstream positions within human core promoters, supporting the existence of DPE-like motifs in human promoters.

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
1553734X and 15537358
Volume :
17
Issue :
8
Database :
Directory of Open Access Journals
Journal :
PLoS Computational Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.78d4bd839e24933a5d03afa2c49c7c6
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pcbi.1009256