Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism

Joseph W Wragg; Paige-Louise White; Yavor Hadzhiev; Kasun Wanigasooriya; Agata Stodolna; Louise Tee; Joao D Barros-Silva; Andrew D Beggs; Ferenc Müller

doi:10.1038/s41594-023-01156-8

Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism

Joseph W Wragg^*, Paige-Louise White, Yavor Hadzhiev, Kasun Wanigasooriya, Agata Stodolna, Louise Tee, Joao D Barros-Silva, Andrew D Beggs^*, Ferenc Müller^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.

Original language	English
Pages (from-to)	1970-1984
Number of pages	15
Journal	Nature Structural and Molecular Biology
Volume	30
Issue number	12
Early online date	23 Nov 2023
DOIs	https://doi.org/10.1038/s41594-023-01156-8
Publication status	Published - Dec 2023

Bibliographical note

Acknowledgements:
We thank The Human Biomaterials Resource Centre (BioBank), Birmingham, for fresh tissue samples and anonymized clinical data. We thank Genomics Birmingham for sequencing. This work was supported by the Wellcome Trust Investigator Award (106955) to F.M., Cancer Research UK, Advanced Clinician Scientist Award (ref. C31641/A23923) to A.B. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We would also like to thank C. Nepal and B. Lenhard for their comments on the manuscript.

Copyright:
© 2023. The Author(s).

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10.1038/s41594-023-01156-8Licence: Creative Commons: Attribution (CC BY)

Wragg J2023IntraFinal published version, 9.88 MBLicence: Creative Commons: Attribution (CC BY)

The core promoter: an unexplored regulatory level of transcription during vertebrate development
Müller, F.
THE WELLCOME TRUST, Imperial College
1/12/15 → 31/10/21
Project: Research

Cite this

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title = "Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism",

abstract = "Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.",

author = "Wragg, {Joseph W} and Paige-Louise White and Yavor Hadzhiev and Kasun Wanigasooriya and Agata Stodolna and Louise Tee and Barros-Silva, {Joao D} and Beggs, {Andrew D} and Ferenc M{\"u}ller",

note = "Acknowledgements: We thank The Human Biomaterials Resource Centre (BioBank), Birmingham, for fresh tissue samples and anonymized clinical data. We thank Genomics Birmingham for sequencing. This work was supported by the Wellcome Trust Investigator Award (106955) to F.M., Cancer Research UK, Advanced Clinician Scientist Award (ref. C31641/A23923) to A.B. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We would also like to thank C. Nepal and B. Lenhard for their comments on the manuscript. Copyright: {\textcopyright} 2023. The Author(s).",

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AU - White, Paige-Louise

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AU - Wanigasooriya, Kasun

AU - Stodolna, Agata

AU - Tee, Louise

AU - Barros-Silva, Joao D

AU - Beggs, Andrew D

AU - Müller, Ferenc

N1 - Acknowledgements: We thank The Human Biomaterials Resource Centre (BioBank), Birmingham, for fresh tissue samples and anonymized clinical data. We thank Genomics Birmingham for sequencing. This work was supported by the Wellcome Trust Investigator Award (106955) to F.M., Cancer Research UK, Advanced Clinician Scientist Award (ref. C31641/A23923) to A.B. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We would also like to thank C. Nepal and B. Lenhard for their comments on the manuscript. Copyright: © 2023. The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.

AB - Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.

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DO - 10.1038/s41594-023-01156-8

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JO - Nature Structural and Molecular Biology

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Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism

Abstract

Bibliographical note

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The core promoter: an unexplored regulatory level of transcription during vertebrate development

Cite this