Redefining transcriptional regulation of the APOE gene and its association with Alzheimer's disease.
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 RN...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0227667 |
| _version_ | 1818843643929165824 |
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| author | Eun-Gyung Lee Jessica Tulloch Sunny Chen Lesley Leong Aleen D Saxton Brian Kraemer Martin Darvas C Dirk Keene Andrew Shutes-David Kaitlin Todd Steve Millard Chang-En Yu |
| author_facet | Eun-Gyung Lee Jessica Tulloch Sunny Chen Lesley Leong Aleen D Saxton Brian Kraemer Martin Darvas C Dirk Keene Andrew Shutes-David Kaitlin Todd Steve Millard Chang-En Yu |
| author_sort | Eun-Gyung Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T05:01:08Z |
| format | Article |
| id | doaj.art-97380ad8d94c4209b91bc28c33be538e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T05:01:08Z |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-97380ad8d94c4209b91bc28c33be538e2022-12-21T20:35:06ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01151e022766710.1371/journal.pone.0227667Redefining transcriptional regulation of the APOE gene and its association with Alzheimer's disease.Eun-Gyung LeeJessica TullochSunny ChenLesley LeongAleen D SaxtonBrian KraemerMartin DarvasC Dirk KeeneAndrew Shutes-DavidKaitlin ToddSteve MillardChang-En YuThe 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.https://doi.org/10.1371/journal.pone.0227667 |
| spellingShingle | Eun-Gyung Lee Jessica Tulloch Sunny Chen Lesley Leong Aleen D Saxton Brian Kraemer Martin Darvas C Dirk Keene Andrew Shutes-David Kaitlin Todd Steve Millard Chang-En Yu Redefining transcriptional regulation of the APOE gene and its association with Alzheimer's disease. PLoS ONE |
| title | Redefining transcriptional regulation of the APOE gene and its association with Alzheimer's disease. |
| title_full | Redefining transcriptional regulation of the APOE gene and its association with Alzheimer's disease. |
| title_fullStr | Redefining transcriptional regulation of the APOE gene and its association with Alzheimer's disease. |
| title_full_unstemmed | Redefining transcriptional regulation of the APOE gene and its association with Alzheimer's disease. |
| title_short | Redefining transcriptional regulation of the APOE gene and its association with Alzheimer's disease. |
| title_sort | redefining transcriptional regulation of the apoe gene and its association with alzheimer s disease |
| url | https://doi.org/10.1371/journal.pone.0227667 |
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