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

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 transcript...

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Autores principales:	René Dreos, Anna Sloutskin, Nati Malachi, Diana Ideses, Philipp Bucher, Tamar Juven-Gershon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/a78d4bd839e24933a5d03afa2c49c7c6
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spelling	oai:doaj.org-article:a78d4bd839e24933a5d03afa2c49c7c62021-12-02T19:58:05ZComputational identification and experimental characterization of preferred downstream positions in human core promoters.1553-734X1553-735810.1371/journal.pcbi.1009256https://doaj.org/article/a78d4bd839e24933a5d03afa2c49c7c62021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009256https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Metazoan 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.René DreosAnna SloutskinNati MalachiDiana IdesesPhilipp BucherTamar Juven-GershonPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 8, p e1009256 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 René Dreos Anna Sloutskin Nati Malachi Diana Ideses Philipp Bucher Tamar Juven-Gershon Computational identification and experimental characterization of preferred downstream positions in human core promoters.
description	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.
format	article
author	René Dreos Anna Sloutskin Nati Malachi Diana Ideses Philipp Bucher Tamar Juven-Gershon
author_facet	René Dreos Anna Sloutskin Nati Malachi Diana Ideses Philipp Bucher Tamar Juven-Gershon
author_sort	René Dreos
title	Computational identification and experimental characterization of preferred downstream positions in human core promoters.
title_short	Computational identification and experimental characterization of preferred downstream positions in human core promoters.
title_full	Computational identification and experimental characterization of preferred downstream positions in human core promoters.
title_fullStr	Computational identification and experimental characterization of preferred downstream positions in human core promoters.
title_full_unstemmed	Computational identification and experimental characterization of preferred downstream positions in human core promoters.
title_sort	computational identification and experimental characterization of preferred downstream positions in human core promoters.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a78d4bd839e24933a5d03afa2c49c7c6
work_keys_str_mv	AT renedreos computationalidentificationandexperimentalcharacterizationofpreferreddownstreampositionsinhumancorepromoters AT annasloutskin computationalidentificationandexperimentalcharacterizationofpreferreddownstreampositionsinhumancorepromoters AT natimalachi computationalidentificationandexperimentalcharacterizationofpreferreddownstreampositionsinhumancorepromoters AT dianaideses computationalidentificationandexperimentalcharacterizationofpreferreddownstreampositionsinhumancorepromoters AT philippbucher computationalidentificationandexperimentalcharacterizationofpreferreddownstreampositionsinhumancorepromoters AT tamarjuvengershon computationalidentificationandexperimentalcharacterizationofpreferreddownstreampositionsinhumancorepromoters
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Computational identification and experimental characterization of preferred downstream positions in human core promoters.

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