DNA methylome and transcriptome sequencing in human ovarian granulosa cells links age-related changes in gene expression to gene body methylation and 3ʹ-end GC density
| Autor: | Stephen Hartley, Alice Ignezweski, Bo Yu, Valya R. Russanova, Silvia Gravina, James C. Mullikin, Bruce H. Howard, James H. Segars, Alan H. DeCherney, J.R. Graham |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Ovarian Granulosa Cell Gene Expression Genomics Biology ovarian granulosa cell DNA sequencing Humans fertility Comparative genomics Genetics DNA methylation Granulosa Cells Ovary Age Factors DNA Epigenome transcription end site Gerotarget (Focus on Aging): Research Paper Oncology Reduced representation bisulfite sequencing CpG Islands Female Human genome Transcriptome Genome-Wide Association Study |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.2875 |
| Popis: | // Bo Yu 1 , Valya R. Russanova 2 , Silvia Gravina 3 , Stephen Hartley 4 , James C. Mullikin 4, 5 , Alice Ignezweski 6 , James Graham 6 , James H. Segars 7 , Alan H. DeCherney 7 , Bruce H. Howard 2 1 Department of Obstetrics and Gynecology & Women's Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA 2 Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA 3 Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA 4 Comparative Genomics Unit, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA 5 NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA 6 Shady Grove Fertility Reproductive Science Center, Rockville, Maryland 20850, USA 7 Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA Correspondence to: Bo Yu, e-mail: boyumich2@gmail.com Keywords: DNA methylation, transcription end site, fertility, ovarian granulosa cell, transcriptome Received: November 14, 2014 Accepted: December 08, 2014 Published: February 17, 2015 ABSTRACT Diminished ovarian function occurs early and is a primary cause for age-related decline in female fertility; however, its underlying mechanism remains unclear. This study investigated the roles that genome and epigenome structure play in age-related changes in gene expression and ovarian function, using human ovarian granulosa cells as an experimental system. DNA methylomes were compared between two groups of women with distinct age-related differences in ovarian functions, using both Methylated DNA Capture followed by Next Generation Sequencing (MethylCap-seq) and Reduced Representation Bisulfite Sequencing (RRBS); their transcriptomes were investigated using mRNA-seq. Significant, non-random changes in transcriptome and DNA methylome features are observed in human ovarian granulosa cells as women age and their ovarian functions deteriorate. The strongest correlations between methylation and the age-related changes in gene expression are not confined to the promoter region; rather, high densities of hypomethylated CpG-rich regions spanning the gene body are preferentially associated with gene down-regulation. This association is further enhanced where CpG regions are localized near the 3'-end of the gene. Such features characterize several genes crucial in age-related decline in ovarian function, most notably the AMH (Anti-Mullerian Hormone) gene. The genome-wide correlation between the density of hypomethylated intragenic and 3'-end regions and gene expression suggests previously unexplored mechanisms linking epigenome structure to age-related physiology and pathology. |
| Databáze: | OpenAIRE |
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