A Novel Application of Mixed Effects Models for Reconciling Base-Pair Resolution 5-Methylcytosine and 5-Hydroxymethylcytosine Data in Neuroepigenetics
| Autor: | Alison I. Bernstein, Joseph Kochmanski, Candace L. Savonen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
neuroepigenetics lcsh:QH426-470 Computer science Base pair mixed effects model for repeated measures Context (language use) Computational biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Hypothesis and Theory Genetics Epigenetics 5-hydroxymethylcytosine 5-methylcytosine Genetics (clinical) 5-Hydroxymethylcytosine bioinformatics Bisulfite 5-Methylcytosine lcsh:Genetics 030104 developmental biology CpG site chemistry 030220 oncology & carcinogenesis DNA methylation Molecular Medicine |
| Zdroj: | Frontiers in Genetics, Vol 10 (2019) Frontiers in Genetics |
| ISSN: | 1664-8021 |
| DOI: | 10.3389/fgene.2019.00801/full |
| Popis: | Epigenetic marks operate at multiple chromosomal levels to regulate gene expression, from direct covalent modification of DNA to three-dimensional chromosomal structure. Research has shown that 5-methylcytosine (5-mC) and its oxidized form, 5-hydroxymethylcytosine (5-hmC), are stable epigenetic marks with distinct genomic distributions and separate regulatory functions. In addition, recent data indicate that 5-hmC plays a critical regulatory role in the mammalian brain, emphasizing the importance of considering this alternative DNA modification in the context of neuroepigenetics. Traditional bisulfite (BS) treatment-based methods to measure the methylome are not able to distinguish between 5-mC and 5-hmC, meaning much of the existing literature does not differentiate these two DNA modifications. Recently developed methods, including Tet-assisted bisulfite treatment and oxidative bisulfite treatment, allow for differentiation of 5-hmC and/or 5-mC levels at base-pair resolution when combined with next-generation sequencing or methylation arrays. Despite these technological advances, there remains a lack of clarity regarding the appropriate statistical methods for integration of 5-mC and 5-hmC data. As a result, it can be difficult to determine the effects of an experimental treatment on 5-mC and 5-hmC dynamics. Here, we propose a statistical approach involving mixed effects to simultaneously model paired 5-mC and 5-hmC data as repeated measures. We tested this approach using publicly available BS/oxidative bisulfite-450K array data and showed that our new approach detected far more CpG probes with paired changes in 5-mC and 5-hmC by Alzheimer's disease status (n = 14,183 probes) compared with the overlapping differential probes generated from separate models for each epigenetic mark (n = 68). Of note, all 68 of the overlapping probe IDs from the separate models were also significant in our new modeling approach, supporting the sensitivity of our new analysis method. Using the proposed approach, it will be possible to determine the effects of an experimental treatment on both 5-mC and 5-hmC at the base-pair level. |
| Databáze: | OpenAIRE |
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