Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Bo Yu MD _, Valya R. Russanova, Silvia Gravina, Stephen Hartley, James C. Mullikin, Alice Ignezweski, James Graham, James H. Segars, Alan H. DeCherney and Bruce H. Howard

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Oncotarget. 2015; 6:3627-3643. https://doi.org/10.18632/oncotarget.2875

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Abstract

Bo Yu1, Valya R. Russanova2, Silvia Gravina3, Stephen Hartley4, James C. Mullikin4,5, Alice Ignezweski6, James Graham6, James H. Segars7, Alan H. DeCherney7, Bruce H. Howard2

1Department of Obstetrics and Gynecology & Women's Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA

2Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA

3Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA

4Comparative Genomics Unit, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

5NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

6Shady Grove Fertility Reproductive Science Center, Rockville, Maryland 20850, USA

7Program 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-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.


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