Bivalent promoter hypermethylation in cancer is linked to the H327me3/H3K4me3 ratio in embryonic stem cells.

BACKGROUND: Thousands of mammalian promoters are defined by co-enrichment of the histone tail modifications H3K27me3 (repressive) and H3K4me3 (activating) and are thus termed bivalent. It was previously observed that bivalent genes in human ES cells (hESC) are frequent targets for hypermethylation in human cancers, and depletion of DNA methylation in mouse embryonic stem cells has a marked impact on H3K27me3 distribution at bivalent promoters. However, only a fraction of bivalent genes in stem cells are targets of hypermethylation in cancer, and it is currently unclear whether all bivalent promoters are equally sensitive to DNA hypomethylation and whether H3K4me3 levels play a role in the interplay between DNA methylation and H3K27me3. RESULTS: We report the sub-classification of bivalent promoters into two groups-promoters with a high H3K27me3:H3K4me3 (hiBiv) ratio or promoters with a low H3K27me3:H3K4me3 ratio (loBiv). HiBiv are enriched in canonical Polycomb components, show a higher degree of local intrachromosomal contacts and are highly sensitive to DNA hypomethylation in terms of H3K27me3 depletion from broad Polycomb domains. In contrast, loBiv promoters are enriched in non-canonical Polycomb components, show lower intrachromosomal contacts and are less sensitive to DNA hypomethylation at the same genomic resolution. Multiple systems reveal that hiBiv promoters are more depleted of Polycomb complexes than loBiv promoters following a reduction in DNA methylation, and we demonstrate that H3K27me3 re-accumulates at promoters when DNA methylation is restored. In human cancer, we show that hiBiv promoters lose H3K27me3 and are more susceptible to DNA hypermethylation than loBiv promoters. CONCLUSION: We conclude that bivalency as a general term to describe mammalian promoters is an over-simplification and our sub-classification has revealed novel insights into the interplay between the largely antagonistic presence of DNA methylation and Polycomb systems at bivalent promoters. This approach redefines molecular pathologies underlying disease in which global DNA methylation is aberrant or where Polycomb mutations are present.

Changes in the maternal hypothalamic-pituitary-adrenal axis in pregnancy and postpartum: influences on maternal and fetal outcomes.

Overexposure of the developing fetus to glucocorticoids is hypothesised to be one of the key mechanisms linking early life development with later life disease. The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes dramatic changes during pregnancy and postpartum. Although cortisol levels rise threefold by the third trimester, the fetus is partially protected from high cortisol by activity of the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2). Maternal HPA axis activity and activity of HSD11B2 may be modified by maternal stress and disease allowing greater transfer of glucocorticoids from mother to fetus. Here we review emerging data from human studies linking dysregulation of the maternal HPA axis to outcomes in both the mother and her offspring. For the offspring, greater glucocorticoid exposure is associated with lower birth weight and shorter gestation at delivery. In addition, evidence supports longer term consequences for the offspring including re-setting of the HPA axis and susceptibility to neurodevelopmental problems and cardiometabolic disease. For the mother, the changes in the HPA axis, particularly in the postpartum period, may increase vulnerability to mood disturbances. Further understanding of the changes in the HPA axis during pregnancy and the impact of these changes may ultimately allow early identification of those most at risk of future disease.

Elafin (SKALP/Trappin-2/proteinase inhibitor-3) is produced by the cervix in pregnancy and cervicovaginal levels are diminished in bacterial vaginosis.

OBJECTIVES: To examine cervicovaginal elafin production in pregnancy and determine its relationship in bacterial vaginosis. STUDY DESIGN: Samples of cervicovaginal secretions were collected from women with uncomplicated singleton pregnancies (n = 112) below 20 weeks gestation. Bacterial flora was assessed using Nugent's criteria, and levels of elafin were measured by enzyme-linked immunosorbent serologic assay (ELISA). Elafin expression in the cervix was also examined by immunohistochemistry. In vitro expression of elafin was examined using cervix and vaginal cell lines. RESULTS: Elafin is expressed in the cervical glandular epithelium. Elafin was found in all 112 samples of cervicovaginal secretions and levels were diminished in women with bacterial vaginosis (P < .05). Interleukin 1beta (IL-1beta) stimulated elafin expression in cells derived from the endocervix, but not in those derived from the vaginal epithelium. CONCLUSIONS: Elafin is a component of cervicovaginal secretions in pregnancy, and levels are diminished in bacterial vaginosis. It may be an important component of innate immunity in the lower genital tract.