Redefining transcriptional regulation of the APOE gene and its association with Alzheimer’s disease


Autoři: Eun-Gyung Lee aff001;  Jessica Tulloch aff001;  Sunny Chen aff001;  Lesley Leong aff001;  Aleen D. Saxton aff001;  Brian Kraemer aff001;  Martin Darvas aff003;  C. Dirk Keene aff003;  Andrew Shutes-David aff001;  Kaitlin Todd aff001;  Steve Millard aff001;  Chang-En Yu aff001
Působiště autorů: Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, United States of America aff001;  Department of Medicine, University of Washington, Seattle, WA, United States of America aff002;  Department of Pathology, University of Washington, Seattle, WA, United States of America aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227667

Souhrn

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet the expression of APOE is not clearly understood. For example, it is unclear whether AD patients have elevated or decreased APOE expression or why the correlation levels of APOE RNA and the ApoE protein differ across studies. Likewise, APOE has a single CpG island (CGI) that overlaps with its 3’-exon, and this CGI’s effect is unknown. We previously reported that the APOE CGI is highly methylated in human postmortem brain (PMB) and that this methylation is altered in AD frontal lobe. In this study, we comprehensively characterized APOE RNA transcripts and correlated levels of RNA expression with DNA methylation levels across the APOE CGI. We discovered the presence of APOE circular RNA (circRNA) and found that circRNA and full-length mRNA each constitute approximately one third of the total APOE RNA, with truncated mRNAs likely constituting some of the missing fraction. All APOE RNA species demonstrated significantly higher expression in AD frontal lobe than in control frontal lobe. Furthermore, we observed a negative correlation between the levels of total APOE RNA and DNA methylation at the APOE CGI in the frontal lobe. When stratified by disease status, this correlation was strengthened in controls but not in AD. Our findings suggest a possible modified mechanism of gene action for APOE in AD that involves not only the protein isoforms but also an epigenetically regulated transcriptional program driven by DNA methylation in the APOE CGI.

Klíčová slova:

Alzheimer's disease – Cerebellum – DNA methylation – Gene expression – Messenger RNA – Polymerase chain reaction – Apolipoprotein genes – Frontal lobe


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