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A transcriptional mechanism involving R-loop, m6A modification and RNA abasic sites regulates an enhancer RNA of APOE

Jason A. Watts, Christopher Grunseich, Yesenia Rodriguez, Yaojuan Liu, Dongjun Li, Joshua T Burdick, Alan Bruzel, Robert J. Crouch, Robert W. Mahley, Samuel H. Wilson, View ORCID ProfileVivian G. Cheung
doi: https://doi.org/10.1101/2022.05.01.489793
Jason A. Watts
1Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA
2Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
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Christopher Grunseich
3National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
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Yesenia Rodriguez
4Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
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Yaojuan Liu
5Department of Pediatrics and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
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Dongjun Li
5Department of Pediatrics and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
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Joshua T Burdick
5Department of Pediatrics and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
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Alan Bruzel
5Department of Pediatrics and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
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Robert J. Crouch
6Eunice Kennedy Shriver, Bethesda, MD 20892, USA
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Robert W. Mahley
7Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
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Samuel H. Wilson
4Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
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Vivian G. Cheung
5Department of Pediatrics and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
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  • ORCID record for Vivian G. Cheung
  • For correspondence: jason.watts@nih.gov vgcheung@med.umich.edu
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Abstract

The DNA genetic code and the RNA regulatory code determine phenotypes from gene expression to disease susceptibility. DNA sequence variants lead to phenotypic differences among individuals, while within an individual, RNA dynamically confers cell identity and responds to cellular and environmental signals. To provide regulation for different cell types and conditions, the nucleotides of RNA are modified by hundreds of chemical reactions, and RNA folds into innumerable shapes. To decipher the RNA regulatory code is to understand how RNA sequence and structure respond to cellular needs. Here, we deciphered one part of the RNA code where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We uncovered an enhancer RNA, AANCR, that regulates the transcription and expression of APOE. When AANCR is folded into an R-loop, which is then modified by N6-adenine methylation and N-glycosidic cleavage, it is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in some cell types and under stress, AANCR does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length enhancer that promotes APOE expression. By genetic analysis, we confirmed that AANCR regulates APOE expression. DNA sequence variants in AANCR are associated with APOE expression and also with Alzheimer’s disease. Our data show that DNA and RNA sequence and structure jointly regulate gene expression that influence disease risk.

Highlights

  • m6A, RNA abasic sites and R-loops jointly regulate transcription by pausing RNA Polymerase II.

  • An enhancer RNA regulates APOE expression.

  • Enhancer RNA of APOE modifies susceptibility to Alzheimer’s disease.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# Deceased

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 01, 2022.
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A transcriptional mechanism involving R-loop, m6A modification and RNA abasic sites regulates an enhancer RNA of APOE
Jason A. Watts, Christopher Grunseich, Yesenia Rodriguez, Yaojuan Liu, Dongjun Li, Joshua T Burdick, Alan Bruzel, Robert J. Crouch, Robert W. Mahley, Samuel H. Wilson, Vivian G. Cheung
bioRxiv 2022.05.01.489793; doi: https://doi.org/10.1101/2022.05.01.489793
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A transcriptional mechanism involving R-loop, m6A modification and RNA abasic sites regulates an enhancer RNA of APOE
Jason A. Watts, Christopher Grunseich, Yesenia Rodriguez, Yaojuan Liu, Dongjun Li, Joshua T Burdick, Alan Bruzel, Robert J. Crouch, Robert W. Mahley, Samuel H. Wilson, Vivian G. Cheung
bioRxiv 2022.05.01.489793; doi: https://doi.org/10.1101/2022.05.01.489793

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