EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

Background/Purpose: Premature ovarian failure (POF) affects 1% of women with a largely idiopathic and poorly understood etiology. The objective of this study was to identify specific epigenetic alterations by measuring DNA methylation of gene regulatory regions in women with POF vs. controls. Methods: Blood samples were collected from idiopathic POFpatients (Amenorrhea for at least 3 months and 2 serum FSH levels of > 40mIU/ml obtained > 1 month apart prior to age 40) and control women (CW) (healthy pregnancy after age 37 with out a pregnancy loss). Genomic DNA was extracted from EDTA anticoagulated blood and bisulfite converted for analysis using the Illumina Golden Gate Methylation Panel which measures DNA methylation at 1506 CpG sites in the promoter regions of 807 genes in 10 POF and 12 CW. Candidate genes with altered epigenetic marks between POF and CW at a nominal P-value < 0.05 were identified using a t-testcomparison within the Illumina bead studio software. Genes of interest were further analyzed for quantitative methylation at specific CpG sites using pyrosequencing in 30 POF and 30 CW. Results: Comparison of DNA methylation profiles of our initial POF and CW groups identified several genes with statistically significanthyper- or hypo- methylation in the POF group (P < 0.05), including the Androgen Receptor (AR)promoter region, which was significantly hypermethylated. To further validate these results, DNA methylation of the AR gene promoter was quantified bypryosequencing in a larger group of POF and CW. Pyrosequencing further confirmed a significantly higher DNA methylation of the AR promoter region inPOF vs. CW (P=0.007). Conclusions: This is a novel study identifying epigenetic alterations in POF. The hypermethylation of the AR gene in POF patients may cause decreased level of the AR in these women. This is especially interesting given a recent report of induced POF in AR deficient mice^1. Specific epigenetic markers, as identified by DNA methylation array profiling in blood, may serve as useful biomarkers for POF and other fertility disorders. However, it will need to be determined if these methylation changes are present prior to diagnosis, or are a consequence of menopause itself. Reference: 1.Hiroko S. et al. Premature ovarian failure in androgenreceptor deficient mice. PNAS;103:224-

A role for pectin in the control of cell expansion

Uptake of nutrients and water depends on the growth of roots through elongation of individual cells near the. root tip. Many of the numerous components of Type I primary cell walls, those of dicotyledons and monocotyledons other than grasses (Poaceae), have been determined, and many hypotheses have been proposed for the control of cell expansion. This important aspect of plant growth still needs elucidation, however. A model is proposed in which pectin, which occurs as a calcium (Ca) pectate gel between the load-bearing cellulose microfibrils and xyloglucan (XG) chains, controls the rate at which cells expand. It is considered that the increasing tension generated by the expanding cell is transmitted to interlocked XG chains and cellulose microfibrils. The resulting deformation of the embedded Ca pectate gel elicits the excretion of protons from the cytoplasm, possibly via compounds such as cell wall-associated kinases, that weakens the Ca pectate gel, permitting slippage of XG molecules through the action of expansin. Further slippage is prevented by deformation of the pectic gel, proton diffusion, and the transfer of residual tension to adjacent XG chains. Evidence for this model is based on the effects of pH, Ca, and aluminum (Al) on root elongation and on the reactions of these cations with Ca pectate. This model allows for genetic selection of plants and adaptation of individual plants to root environmental conditions

Forest plots for association of rs2509049 with DLBCL, FL and all B-cell lymphomas.

<p>Squares indicate the ORs, with the sizes proportional to the weight of the study in the meta-analysis. Summary ORs with and without the inclusion of the BC population are indicated in bold and designated with a diamond extending the width of the CI. All p values are from a fixed effects model except those indicated with an asterisk (*) which are from a random effects model. <i>Q</i> values for analyses including the BC dataset for DLBCL, FL and All B cell groups are <i>Q</i>=0.876, <i>Q</i>=0.053 and <i>Q</i>=0.161 for combined sexes, and <i>Q</i>=0.344, <i>Q</i>=0.045 and <i>Q</i>=0.002 for females only, respectively. Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; all B-cell, all B-cell lymphomas; SCALE, Scandinavian Lymphoma Etiology; SF, San Francisco; BC, British Columbia; NCI-SEER, National Cancer Institute - Surveillance, Epidemiology and End Results; NSW, New South Wales. Figure created with rmeta version 2.16.</p

Linkage Disequilibrium for 13 SNPs in 1115 cases and controls in the BC population.

<p>Chromosomal coordinates (Hg18) and Entrez genes are mapped relative to the 13 SNPs analyzed in this study. The linkage disequilibrium plot shows <i>r</i>² values; predicted haplotype blocks are outlined in black. Figure created with Haploview version 4.2.</p