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The dysregulation of enhancers leads to diseases collectively termed enhanceropathies. While it is known that enhancers play a role in diseases by regulating gene expression, the specific mechanisms by which individual enhancers cause diseases are not well understood. Studies of individual enhancers are needed to fill this gap. This study delves into the role of APOE-activating noncoding RNA, AANCR, in the central nervous system, elucidating its function as a genetic modifier in Alzheimer's Disease. We employed RNA interference, RNaseH-mediated degradation, and single-molecule RNA fluorescence in situ hybridization to demonstrate that mere transcription of AANCR is insufficient; rather, its transcripts are crucial for promoting APOE expression. Our findings revealed that AANCR is induced by ATM-mediated ERK phosphorylation and subsequent AP-1 transcription factor activation. Once activated, AANCR enhances APOE expression, which in turn imparts an inflammatory phenotype to astrocytes. These findings demonstrate that AANCR is a key enhancer RNA in some cell types within the nervous system, pivotal for regulating APOE expression and influencing inflammatory responses, underscoring its potential as a therapeutic target in neurodegenerative diseases.<\/jats:p>","DOI":"10.1093\/nar\/gkae696","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T11:03:36Z","timestamp":1724151816000},"page":"10235-10254","source":"Crossref","is-referenced-by-count":10,"title":["The enhancer RNA, AANCR, regulates APOE expression in astrocytes and microglia"],"prefix":"10.1093","volume":"52","author":[{"given":"Ma","family":"Wan","sequence":"first","affiliation":[{"name":"Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC\u00a0 27709 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaojuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Michigan , Ann Arbor , MI\u00a0 48109 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Michigan , Ann Arbor , MI\u00a0 48109 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan\u00a0J","family":"Snyder","sequence":"additional","affiliation":[{"name":"Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC\u00a0 27709 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian\u00a0B","family":"Elkin","sequence":"additional","affiliation":[{"name":"Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC\u00a0 27709 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher\u00a0R","family":"Day","sequence":"additional","affiliation":[{"name":"Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC\u00a0 27709 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6017-1376","authenticated-orcid":false,"given":"Joseph","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC\u00a0 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\u00a0 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert\u00a0W","family":"Mahley","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Neurological Disease , San Francisco , CA , USA"},{"name":"Department of Pathology and Medicine, University of California , San Francisco , CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6584-6961","authenticated-orcid":false,"given":"Jason\u00a0A","family":"Watts","sequence":"additional","affiliation":[{"name":"Epigenetics and Stem Cell Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC\u00a0 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, University of Michigan , Ann Arbor , MI\u00a0 48109 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,20]]},"reference":[{"key":"2024092307452832500_B1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.cell.2018.11.029","article-title":"A genome-wide framework for mapping gene regulation via cellular genetic screens","volume":"176","author":"Gasperini","year":"2019","journal-title":"Cell"},{"key":"2024092307452832500_B2","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1016\/j.molcel.2022.04.009","article-title":"Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome","volume":"82","author":"Martinez-Ara","year":"2022","journal-title":"Mol. 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