Endometriosis affects approximately 10% of young, reproductive-aged women. Disease associated pelvic pain; infertility and sexual dysfunction have a significant adverse clinical, social and financial impact. As precise disease etiology has remained elusive, current therapeutic strategies are empiric, unfocused and often unsatisfactory. Lack of a suitable genetic model has impaired further translational research in the field. In this study, we evaluated the role of the Sp/KLF transcription factor KLF11/Klf11 in the pathogenesis of endometriosis. KLF11, a human disease-associated gene is etiologically implicated in diabetes, uterine fibroids and cancer. We found that KLF11 expression was diminished in human endometriosis implants and further investigated its pathogenic role in Klf11-/- knockout mice with surgically induced endometriotic lesions. Lesions in Klf11-/- animals were large and associated with prolific fibrotic adhesions resembling advanced human disease in contrast to wildtype controls. To determine phenotype-specificity, endometriosis was also generated in Klf9-/- animals. Unlike in Klf11-/- mice, lesions in Klf9-/- animals were neither large, nor associated with a significant fibrotic response. KLF11 also bound to specific elements located in the promoter regions of key fibrosis-related genes from the Collagen, MMP and TGF-β families in endometrial stromal cells. KLF11 binding resulted in transcriptional repression of these genes. In summary, we identify a novel pathogenic role for KLF11 in preventing de novo disease-associated fibrosis in endometriosis. Our model validates in vivo the phenotypic consequences of dysregulated Klf11 signaling. Additionally, it provides a robust means not only for further detailed mechanistic investigation but also the ability to test any emergent translational ramifications thereof, so as to expand the scope and capability for treatment of endometriosis.

Background: KLF16 is the least characterized family member of recently described metabolic regulators.Results: We extensively characterize mechanisms of DNA binding and chromatin coupling used by KLF16 to regulate metabolic gene expression.Conclusion: KLF16 is a novel regulator of metabolic genes by regulatable coupling to Sin3-histone deacetylase complexes.Significance: This knowledge reveals key mechanisms used by KLF16 as a regulator of metabolic gene expression.

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Prospective cohort study. MATERIALS AND METHODS: We followed 93,775 women participating in the Nurses' Health Study II between 1991 and 2013 who had no prior history of cardiovascular disease, cancer, or diabetes and who reported the usual length and regularity of their menstrual cycles at ages of 14-17, 18-22, and 28-48 years. We obtained hazard ratios (HR) and 95% confidence intervals (CI) for the relationships between menstrual cycle characteristics and mortality from Cox proportional hazards models adjusted for relevant confounders including body mass index, race/ethnicity, and physical activity, and lifestyle factors.RESULTS: We documented 1679 deaths, including 828 from cancer, and 166 from cardiovascular disease, during 1,729,410 person-years of followup. After adjustment for various covariates, women reported that their menstrual cycles were always irregular between the ages of 14-17 and 18-22 were 21% [HR¼1.21 (95% CI: 1.04, 1.40)] and 34% [HR¼1.34 (95% CI: 1.08, 1.66)], respectively, more likely to die from any causes during follow-up than women reporting very regular menstrual cycles in the same age range. A similar relation was observed with irregular menstrual cycles between the ages of 28-48 years. Likewise, women reporting a current usual cycle length of 32-39 days or of R40 days were more likely to die from any causes during follow-up than women whose current usual cycle length was 26-31 days [HRs ¼1.23 (95% CI: 1.04, 1.45), and 1.28 (95% CI: 1.05, 1.55), respectively]. Elevated HR for cardiovascular and cancer mortality was also associated with longer menstrual cycle lengths (>32 days) between the ages of 28-48 years.CONCLUSIONS: Irregular and long menstrual cycles are associated with an increased risk of mortality.

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