scholarly journals A distinctive epigenetic ageing profile in human granulosa cells

2020 ◽  
Vol 35 (6) ◽  
pp. 1332-1345
Author(s):  
K W Olsen ◽  
J Castillo-Fernandez ◽  
A Zedeler ◽  
N C Freiesleben ◽  
M Bungum ◽  
...  
Keyword(s):  
Gene Expression ◽  
Granulosa Cells ◽  
Ovarian Stimulation ◽  
Collaborative Study ◽  
Somatic Cells ◽  
Chronological Age ◽  
Methylation Array ◽  
Healthy Women ◽  
Age Related ◽  
A Genome

Abstract STUDY QUESTION Does women’s age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells? SUMMARY ANSWER Accumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile. WHAT IS KNOWN ALREADY The mechanisms underlying the decline in women’s fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa). STUDY DESIGN, SIZE, DURATION This study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS Blood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package. MAIN RESULTS AND ROLE OF CHANCE Using established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7 years) compared to chronological age (average: 33.9 years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4 years) and leukocytes (average: 38.8 years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P = 0.003) but predicted telomere lengths unaffected by age (Pearson’s correlation coefficient = −0.1, P = 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n = 335) and in leukocytes (n = 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P = 3.96 × 10−08) and gene expression (152 genes, P = 2.3 × 10−06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION No gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found. WIDER IMPLICATIONS OF THE FINDINGS Our findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age. STUDY FUNDING/COMPETING INTEREST(S) This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest.

scholarly journals Epigenetic clock and methylation studies in the rhesus macaque

GeroScience ◽  
2021 ◽  
Author(s):  
Steve Horvath ◽  
Joseph A. Zoller ◽  
Amin Haghani ◽  
Anna J. Jasinska ◽  
Ken Raj ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Rhesus Macaque ◽  
Mammalian Species ◽  
Vervet Monkey ◽  
Chronological Age ◽  
Biological Research ◽  
Epigenetic Clock ◽  
Methylation Array ◽  
Tissue Samples ◽  
Age Related

AbstractMethylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n = 281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regard to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation (R = 0.89) with the vervet monkey (Chlorocebus sabaeus), another Old World species. Four CpGs within the KLF14 promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). Future studies will be needed to evaluate whether these epigenetic clocks predict age-related conditions in the rhesus macaque.

scholarly journals The Orphan Nuclear Receptors NURR1 and NGFI-B Modulate Aromatase Gene Expression in Ovarian Granulosa Cells: A Possible Mechanism for Repression of Aromatase Expression upon Luteinizing Hormone Surge

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 237-246 ◽  
Author(s):  
Yimin Wu ◽  
Sagar Ghosh ◽  
Yoshihiro Nishi ◽  
Toshihiko Yanase ◽  
Hajime Nawata ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Granulosa Cells ◽  
Intracellular Camp ◽  
Orphan Nuclear Receptors ◽  
Aromatase Gene ◽  
Ovarian Granulosa Cells ◽  
A Genome ◽  
Responsive Gene ◽  
Aromatase Gene Expression

Ovarian granulosa cells play pivotal roles in many aspects of ovary functions including folliculogenesis and steroidogenesis. In response to FSH and LH, the elevation of intracellular cAMP level in granulosa cells leads to activation of multiple ovarian genes. Here, we report findings from a genome-wide study of the cAMP-responsive gene expression profiles in a human granulosa-like tumor cell line, KGN. The study identified 140 genes that are either activated or repressed by 2-fold or greater after stimulation by the adenylyl cyclase activator forskolin. The induction patterns of some cAMP-responsive genes were further analyzed by quantitative real-time PCR. Consistent with previous observations, the LH-responsive genes, such as the nuclear receptor 4A subfamily (NURR1, NGFI-B, and NOR-1), were rapidly but transiently induced, whereas the FSH-responsive gene CYP19 encoding aromatase was induced in a delayed fashion. Interestingly, ectopic expression of NURR1 or NGFI-B severely attenuated the cAMP-responsive activation of the ovary-specific aromatase promoter. Reduction of the endogenous NURR1 or NGFI-B by small interfering RNA significantly elevated aromatase gene expression. The cis-elements responsible for NURR1/NGFI-B-mediated repression were mapped to the minimal aromatase promoter sequence that confers camp responsiveness. Furthermore, the DNA-binding domain of NURR1 was required for the repression. Taken together, these results strongly suggest a causal relationship between the rapid decline of aromatase mRNA and induction of nuclear receptor subfamily 4A expression, which concomitantly occur upon LH surge at the later stages of ovarian follicular development.

scholarly journals Age-dependent changes in mean and variance of gene expression across tissues in a twin cohort

2016 ◽  
Author(s):  
Ana Viñuela ◽  
Andrew A Brown ◽  
Alfonso Buil ◽  
Pei-Chien Tsai ◽  
Matthew N Davies ◽  
...  
Keyword(s):  
Gene Expression ◽  
Healthy Aging ◽  
Process Analysis ◽  
Strong Relationship ◽  
Methylation Array ◽  
Age Related ◽  
Age Dependent ◽  
Mean And Variance ◽  
The Relationship ◽  
Age Related Changes

AbstractGene expression changes with age have consequences for healthy aging and disease development. Here we investigate age-related changes in gene expression measured by RNA-seq in four tissues and the interplay between genotypes and age-related changes in expression. Using concurrently measured methylation array data from fat we also investigate the relationship between methylation, gene expression and age. We identified age-dependent changes in mean levels of gene expression in 5,631 genes and in splicing of 904 genes. Age related changes were widely shared across tissues, with up to 60% of age-related changes in expression and 47% on splicing in multi-exonic genes shared; amongst these we highlight effects on genes involved in diseases such as Alzheimer and cancer. We identified 137 genes with age-related changes in variance and 42 genes with age-dependent discordance between genetically identical individuals; implying the latter are driven by environmental effects. We also give four examples where genetic control of expression is affected by the aging process. Analysis of methylation observed a widespread and stronger effect of age on methylation than expression; however we did not find a strong relationship between age-related changes in both expression and methylation. In summary, we quantified aging affects in splicing, level and variance of gene expression, and show that these processes can be both environmentally and genetically influenced.

Caspase-3 gene expression in human luteinized granulosa cells is inversely correlated with the number of oocytes retrieved after controlled ovarian stimulation

2017 ◽  
Vol 22 (1) ◽  
pp. 33-38 ◽  
Author(s):  
Verônica N. Lobach ◽  
Maíra Casalechi ◽  
Cynthia Dela Cruz ◽  
Maria T. Pereira ◽  
Helen L. Del Puerto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Granulosa Cells ◽  
Ovarian Stimulation ◽  
Caspase 3 ◽  
Controlled Ovarian Stimulation

scholarly journals The effect of age on DNA methylation in whole blood among Bangladeshi men and women

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Rick J. Jansen ◽  
Lin Tong ◽  
Maria Argos ◽  
Farzana Jasmine ◽  
Muhammad Rakibuz-Zaman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Cpg Islands ◽  
Chronological Age ◽  
Cpg Sites ◽  
Age Related ◽  
Genome Wide ◽  
A Genome ◽  
Effect Of Age ◽  
Age Related Changes

Abstract Background It is well-known that methylation changes occur as humans age, however, understanding how age-related changes in DNA methylation vary by sex is lacking. In this study, we characterize the effect of age on DNA methylation in a sex-specific manner and determine if these effects vary by genomic context. We used the Illumina HumanMethylation 450 K array and DNA derived from whole blood for 400 adult participants (189 males and 211 females) from Bangladesh to identify age-associated CpG sites and regions and characterize the location of these age-associated sites with respect to CpG islands (vs. shore, shelf, or open sea) and gene regions (vs. intergenic). We conducted a genome-wide search for age-associated CpG sites (among 423,604 sites) using a reference-free approach to adjust for cell type composition (the R package RefFreeEWAS) and performed an independent replication analysis of age-associated CpGs. Results The number of age-associated CpGs (p < 5 x 10− 8) were 986 among men and 3479 among women of which 2027(63.8%) and 572 (64.1%) replicated (using Bonferroni adjusted p < 1.2 × 10− 5). For both sexes, age-associated CpG sites were more likely to be hyper-methylated with increasing age (compared to hypo-methylated) and were enriched in CpG islands and promoter regions compared with other locations and all CpGs on the array. Although we observed strong correlation between chronological age and previously-developed epigenetic age models (r ≈ 0.8), among our top (based on lowest p-value) age-associated CpG sites only 12 for males and 44 for females are included in these prediction models, and the median chronological age compared to predicted age was 44 vs. 51.7 in males and 45 vs. 52.1 in females. Conclusions Our results describe genome-wide features of age-related changes in DNA methylation. The observed associations between age and methylation were generally consistent for both sexes, although the associations tended to be stronger among women. Our population may have unique age-related methylation changes that are not captured in the established methylation-based age prediction model we used, which was developed to be non-tissue-specific.

scholarly journals Development and Application of a Rat Ovarian Gene Expression Database

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5384-5396 ◽  
Author(s):  
Misung Jo ◽  
Mary C. Gieske ◽  
Charles E. Payne ◽  
Sarah E. Wheeler-Price ◽  
Joseph B. Gieske ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chorionic Gonadotropin ◽  
Granulosa Cells ◽  
Human Chorionic Gonadotropin ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Expression Database ◽  
Total Rna ◽  
A Genome ◽  
Six Genes

Abstract The pituitary gonadotropins play a key role in follicular development and ovulation through the induction of specific genes. To identify these genes, we have constructed a genome-wide rat ovarian gene expression database (rOGED). The database was constructed from total RNA isolated from intact ovaries, granulosa cells, or residual ovarian tissues collected from immature pregnant mare serum gonadotropin (PMSG)/human chorionic gonadotropin-treated rats at 0 h (no PMSG), 12 h, and 48 h post PMSG, as well as 6 and 12 h post human chorionic gonadotropin. The total RNA was used for DNA microarray analysis using Affymetrix Rat Expression Arrays 230A and 230B (Affymetrix, Santa Clara, CA). The microarray data were compiled and used for display of individual gene expression profiles through specially developed software. The final rOGED provides immediate analysis of temporal gene expression profiles for over 28,000 genes in intact ovaries, granulosa cells, and residual ovarian tissue during follicular growth and the preovulatory period. The accuracy of the rOGED was validated against the gene profiles for over 20 known genes. The utility of the rOGED was demonstrated by identifying six genes that have not been described in the rat periovulatory ovary. The mRNA expression patterns and cellular localization for each of these six genes (estrogen sulfotransferase, synaptosomal-associated protein 25 kDa, runt-related transcription factor, calgranulin B, α1-macroglobulin, and MAPK phosphotase-3) were confirmed by Northern blot analyses and in situ hybridization, respectively. The current findings demonstrate that the rOGED can be used as an instant reference for ovarian gene expression profiles, as well as a reliable resource for identifying important yet, to date, unknown ovarian genes.

scholarly journals Age-related Gene Expression Signatures (AGES) in rats demonstrate early, late, and linear transcriptional changes from multiple tissues

2019 ◽  
Author(s):  
Tea Shavlakadze ◽  
Melody Morris ◽  
Jian Fang ◽  
Sharon X. Wang ◽  
Weihua Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Signature ◽  
Chronological Age ◽  
Related Gene ◽  
Age Related ◽  
Number Of Genes ◽  
Organ Specific ◽  
Transcriptional Changes ◽  
Effects Of Aging ◽  
Early Late

SUMMARYIn order to understand changes in gene expression that occur as a result of age, which might create a permissive or causal environment for age-related diseases, we produced a multi-timepoint Age-related Gene Expression Signature (AGES) from liver, kidney, skeletal muscle and hippocampus of rats, comparing 6, 9, 12, 18, 21, 24 and 27-month old animals. We focused on genes that changed in one direction throughout the lifespan of the animal, either early in life (early logistic changes); at mid-age (mid-logistic); late in life (late-logistic); or linearly, throughout the lifespan. The pathways perturbed as a result of chronological age demonstrate organ-specific and more global effects of aging, and point to mechanisms that might be counter-regulated pharmacologically in order to treat age-associated diseases. A small number of genes were regulated by aging in the same manner in every tissue, suggesting they may be more universal markers of aging.

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