{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T15:12:17Z","timestamp":1767193937893,"version":"3.48.0"},"reference-count":83,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T00:00:00Z","timestamp":1766793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merit Review Awards","award":["BX000933"],"award-info":[{"award-number":["BX000933"]}]},{"name":"Merit Review Awards","award":["BX004823"],"award-info":[{"award-number":["BX004823"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The \u03b54 allele of the apolipoprotein E (APOE) gene strongly increases Alzheimer\u2019s disease (AD) risk, though its molecular mechanisms remain unclear. AD-associated genetic signals also extend to neighboring genes TOMM40 and APOC1, suggesting a complex cis-regulatory landscape. To investigate chromatin architecture and its impact on gene regulation across this region, we performed chromosome conformation capture in human cell lines and postmortem brain tissues, consistently identifying TOMM40\u2013APOE and APOE\u2013APOC1 interactions. We further developed a digital PCR assay to quantify APOE\u2013APOC1 interaction strength and measured APOC1 mRNA via RT-qPCR. Enhanced chromatin interaction correlated with elevated APOC1 transcription in AD specimens. Genotypic analysis showed that \u03b53\/\u03b54 carriers had strong chromatin interaction and transcriptional activation, whereas \u03b54\/\u03b54 homozygotes exhibited minimal chromatin remodeling despite similar APOC1 expression, suggesting a decoupling of chromatin architecture and transcriptional output. These findings underscore the interplay of AD status, APOE genotype, and locus-specific chromatin dynamics in disease susceptibility. Integration of 3D genome topology with transcriptomic profiling offers a framework to study APOE-related disorders and supports broader application across neurodegenerative loci for genotype-guided therapy development.<\/jats:p>","DOI":"10.3390\/ijms27010302","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T05:28:19Z","timestamp":1766986099000},"page":"302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interplay Between 3D Chromatin Architecture and Gene Regulation at the APOE Locus Contributes to Alzheimer\u2019s Disease Risk"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2357-5531","authenticated-orcid":false,"given":"Eun-Gyung","family":"Lee","sequence":"first","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley","family":"Leong","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5230-2823","authenticated-orcid":false,"given":"Sunny","family":"Chen","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Tulloch","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6967-026X","authenticated-orcid":false,"given":"Chang-En","family":"Yu","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/mp.2012.159","article-title":"A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing","volume":"19","author":"Davies","year":"2014","journal-title":"Mol. 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