title: DNA methylome and transcriptome sequencing in human ovarian granulosa cells links age-related changes in gene expression to gene body methylation and 3'-end GC density.
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-Müllerian 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.
authors: Department of Obstetrics and Gynecology & Women's Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors: Bo
authors: B
authors: Yu
authors: Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Valya R
authors: VR
authors: Russanova
authors: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors: Silvia
authors: S
authors: Gravina
authors: Comparative Genomics Unit, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Stephen
authors: S
authors: Hartley
authors: Comparative Genomics Unit, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.|NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: James C
authors: JC
authors: Mullikin
authors: Shady Grove Fertility Reproductive Science Center, Rockville, Maryland 20850, USA.
authors: Alice
authors: A
authors: Ignezweski
authors: Shady Grove Fertility Reproductive Science Center, Rockville, Maryland 20850, USA.
authors: James
authors: J
authors: Graham
authors: 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.
authors: James H
authors: JH
authors: Segars
authors: 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.
authors: Alan H
authors: AH
authors: DeCherney
authors: Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Bruce H
authors: BH
authors: Howard
mesh_terms: D000328:Adult; D000367:Age Factors; D018899:CpG Islands; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006107:Granulosa Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D010053:Ovary / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D059467:Transcriptome
chemical_list: D004247:DNA