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

Autor: Lesley Leong, Steve Millard, Kaitlin Todd, Jessica Tulloch, Andrew Shutes-David, Martin Darvas, Brian C. Kraemer, Aleen D. Saxton, Eun Gyung Lee, Chang En Yu, C. Dirk Keene, Sunny Chen
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Apolipoprotein E
Artificial Gene Amplification and Extension
Alzheimer's Disease
Biochemistry
Polymerase Chain Reaction
0302 clinical medicine
Cerebellum
Gene expression
Medicine and Health Sciences
Transcriptional regulation
Aged
80 and over
Cerebral Cortex
Regulation of gene expression
DNA methylation
Multidisciplinary
Messenger RNA
Brain
Neurodegenerative Diseases
Chromatin
Frontal Lobe
Nucleic acids
Neurology
Medicine
Female
Epigenetics
lipids (amino acids
peptides
and proteins)
Autopsy
Anatomy
DNA modification
Chromatin modification
Research Article
Chromosome biology
Cell biology
medicine.medical_specialty
Lipoproteins
Science
Biology
Research and Analysis Methods
Polymorphism
Single Nucleotide
Apolipoprotein Genes
03 medical and health sciences
Apolipoproteins E
Alzheimer Disease
Circular RNA
Internal medicine
Mental Health and Psychiatry
Genetics
medicine
Humans
Genetic Predisposition to Disease
RNA
Messenger
Molecular Biology Techniques
Molecular Biology
Aged
Biology and life sciences
Proteins
RNA
RNA
Circular
DNA
030104 developmental biology
Endocrinology
Gene Expression Regulation
Case-Control Studies
CpG Islands
Dementia
030217 neurology & neurosurgery
Zdroj: PLoS ONE, Vol 15, Iss 1, p e0227667 (2020)
PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0227667
Popis: 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.
Databáze: OpenAIRE
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