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However, the regulatory role of RNA sequence and structure and how dysregulation leads to diseases remain largely unknown. Here, we uncovered a mechanism where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We found an enhancer RNA, AANCR, that regulates the transcription and expression of apolipoprotein E (APOE). In some human cells such as fibroblasts, AANCR is folded into an R-loop and modified by N-glycosidic cleavage; in this form, AANCR is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in other cell types including hepatocytes 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. DNA sequence variants in AANCR are associated significantly with APOE expression and Alzheimer's Disease, thus AANCR is a modifier of Alzheimer's Disease. Besides AANCR, thousands of noncoding RNAs are regulated by abasic sites in R-loops. Together our data reveal the essentiality of the folding and modification of RNA in cellular regulation and demonstrate that dysregulation underlies common complex diseases such as Alzheimer's disease.<\/jats:p>","DOI":"10.1093\/nar\/gkac1107","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T08:13:19Z","timestamp":1667895199000},"page":"12497-12514","source":"Crossref","is-referenced-by-count":38,"title":["A common transcriptional mechanism involving R-loop and RNA abasic site regulates an enhancer RNA of\n                    <i>APOE<\/i>"],"prefix":"10.1093","volume":"50","author":[{"given":"Jason A","family":"Watts","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Michigan , Ann Arbor, MI 48109, USA"},{"name":"Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1857-928X","authenticated-orcid":false,"given":"Christopher","family":"Grunseich","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yesenia","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaojuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Life Sciences Institute, University of Michigan , Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Life Sciences Institute, University of Michigan , Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua\u00a0T","family":"Burdick","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Life Sciences Institute, University of Michigan , Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Bruzel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Life Sciences Institute, University of Michigan , Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J","family":"Crouch","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W","family":"Mahley","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Neurological Disease , San Francisco, CA, USA"},{"name":"Departments of Pathology and Medicine, University of California , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel\u00a0H","family":"Wilson","sequence":"additional","affiliation":[{"name":"Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4029-6243","authenticated-orcid":false,"given":"Vivian\u00a0G","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Life Sciences Institute, University of Michigan , Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"2022121615501692000_B1","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/nature04244","article-title":"Mapping determinants of human gene expression by regional and genome-wide association","volume":"437","author":"Cheung","year":"2005","journal-title":"Nature"},{"key":"2022121615501692000_B2","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nature02797","article-title":"Genetic analysis of genome-wide variation in human gene expression","volume":"430","author":"Morley","year":"2004","journal-title":"Nature"},{"key":"2022121615501692000_B3","doi-asserted-by":"crossref","first-page":"D303","DOI":"10.1093\/nar\/gkx1030","article-title":"MODOMICS: a database of RNA modification pathways. 2017 update","volume":"46","author":"Boccaletto","year":"2018","journal-title":"Nucleic. 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