Abnormal methylation of PRDM16 and PTPRN2 genes in chorionic villi in miscarriage

Relevance. Abnormal epigenetic regulation of genes responsible for the development of the embryo and placenta is associated with many pregnancy pathologies. Aim. The aim of this work was to analyze the prevalence of abnormal methylation of the PRDM16 and PTPRN2 genes in chorionic villi of spontaneous abortions with normal karyotype and with the most frequent aneuploidies (trisomy 16 and monosomy X). Materials and Methods. The methylation profile was evaluated using targeted bisulfite massive parallel sequencing in chorionic villi of induced abortions (n = 10), spontaneous abortions with normal karyotype (n = 39), trisomy 16 (n = 17) and monosomy X (n = 20) and peripheral blood lymphocytes of healthy volunteers (n = 6). Results and Discussion. In analyzed genes, differential methylation of individual CpG sites was found in chorionic villi of spontaneous abortions. Despite the absence of significant differences between the groups in the average level of methylation in analyzed gene regions, abnormal methylation of the PRDM16 and PTPRN2 genes were detected for 33 % and 5 % of spontaneous abortions, respectively, indicating a high incidence of epigenetic abnormalities in these genes in the chorionic villi of spontaneous abortions. The level of methylation of the PRDM16 gene significantly correlated with the level of methylation of the retrotransposon LINE-1, which indicates the generalized nature of methylation disorders in spontaneous abortions. Finally, the level of methylation of the PTPRN2 gene depended on the age of mothers of spontaneous abortions with monosomy X, which raises the question of the influence of maternal factors on the methylation profile in this group of spontaneous abortions. Conclusion. The results indicate that epigenetic disorders of the PRDM16 gene may be associated with spontaneous termination of pregnancy in the first trimester

LINE-1 retrotransposon methylation in chorionic villi of first trimester miscarriages with aneuploidy

Purpose High frequency of aneuploidy in meiosis and cleavage stage coincides with waves of epigenetic genome reprogramming that may indicate a possible association between epigenetic mechanisms and aneuploidy occurrence. This study aimed to assess the methylation level of the long interspersed repeat element 1 (LINE-1) retrotransposon in chorionic villi of first trimester miscarriages with a normal karyotype and aneuploidy. Methods The methylation level was assessed at 19 LINE-1 promoter CpG sites in chorionic villi of 141 miscarriages with trisomy of chromosomes 2, 6, 8-10, 13-15, 16, 18, 20-22, and monosomy X using massive parallel sequencing. Results The LINE-1 methylation level was elevated statistically significant in chorionic villi of miscarriages with both trisomy (45.2 +/- 4.3%) and monosomy X (46.9 +/- 4.2%) compared with that in induced abortions (40.0 +/- 2.4%) (p < 0.00001). The LINE-1 methylation levels were specific for miscarriages with different aneuploidies and significantly increased in miscarriages with trisomies 8, 14, and 18 and monosomy X (p < 0.05). The LINE-1 methylation level increased with gestational age both for group of miscarriages regardless of karyotype (R = 0.21, p = 0.012) and specifically for miscarriages with trisomy 16 (R = 0.48, p = 0.007). LINE-1 methylation decreased with maternal age in miscarriages with a normal karyotype (R = - 0.31, p = 0.029) and with trisomy 21 (R = - 0.64, p = 0.024) and increased with paternal age for miscarriages with trisomy 16 (R = 0.38, p = 0.048) and monosomy X (R = 0.73, p = 0.003). Conclusion Our results indicate that the pathogenic effects of aneuploidy in human embryogenesis can be supplemented with significant epigenetic changes in the repetitive sequences

ФАКТОРЫ РИСКА СЕРДЕЧНО-СОСУДИСТЫХ ЗАБОЛЕВАНИЙ И ЦЕНТРАЛЬНОЙ ГЕМОДИНАМИКИ У СТУДЕНТОВ-СТАРШЕКУРСНИКОВ

HighlightsThe article examines the prevalence of risk factors for cardiovascular diseases (CVD) and the state of central hemodynamics (CHD) in senior students. Aim. To study the risk factors for CHD and CVD in senior students with the aim of early detection of arterial hypertension (AH) and the implementation of therapeutic and prophylactic measures.Methods. The study involved 223 senior students of medical universities in Moscow aged 20-27 years (the mean age was 22.8±0.17 years). The following cardiovascular risk factors were assessed for each student: age, gender, smoking, physical activity, genetic predispositions; body mass index. The indicators of CHD were studied by volumetric compression oscillometry using a portable automated software-hardware complex for non-invasive research of central hemodynamics (“SHCNIR CHD vco-“Globus” device).Results. The presence of CVD risk factors in senior students was revealed in 52.5% of cases; more than two risk factors were found in 19.3% of cases; 1st degree arterial hypertension (AH) in 11.2% of cases; “white coat hypertension” in 10.8% of cases; genetic predisposition to CVD in 30.0% of cases; overweight in 17.0% of cases; obesity in 5.4% of cases; low physical activity in 23.8% of cases; smoking in 16.1% of cases. An altered CHD profile was found in 62.1% of students. An increase in total peripheral vascular resistance at normal blood pressure levels was noted in 31.8% of cases. Indicators of total peripheral vascular resistance, mean blood pressure, systolic and diastolic blood pressure were significantly higher in the group of students with CHD risk factors.Conclusion. Outpatient follow-up groups should include students with established risk factors for cardiovascular diseases, diagnosed AH, and with altered indicators of CHD. Preventive examinations should include a simple method for studying hemodynamics – compression oscillometry.Основные положенияВ статье исследованы частота факторов риска развития сердечно-сосудистых заболеваний и состояние центральной гемодинамики у студентов старших курсов. Цель. Изучить основные факторы риска сердечно-сосудистых заболеваний (ФР ССЗ) и центральной гемодинамики (ЦГД) у студентов-старшекурсников.Материалы и методы. Обследованы 223 студента старших курсов медицинских вузов Москвы в возрасте 20–27 лет (средний возраст составил 22,8±0,17 года). У каждого студента оценены основные ФР ССЗ: возраст, пол, курение, физическая активность, наследственность, индекс массы тела. Показатели ЦГД исследованы методом объемной компрессионной осциллометрии с помощью портативного автоматизированного программно-аппаратного комплекса неинвазивного исследования центральной гемодинамики (прибор «КАП ЦГ осм-«Глобус»).Результаты. ФР ССЗ выявлены у 52,5% студентов старших курсов, более двух факторов риска обнаружено у 19,3%. Артериальная гипертензия I степени зарегистрирована у 11,2% лиц, артериальная гипертензия «белого халата» – у 10,8%, отягощенная наследственность – у 30,0%, избыточная масса тела – у 17,0%, ожирение – у 5,4%, гиподинамия – у 3,8%, курение – у 16,1% обследованных. Измененный профиль ЦГД обнаружен у 62,1% студентов. Повышение общего периферического сосудистого сопротивления при нормальных уровнях артериального давления определено у 31,8% лиц. Показатели общего периферического сосудистого сопротивления, среднего, систолического и диастолического артериального давления были достоверно выше в группе студентов с ФР ССЗ.Заключение. В группу диспансерного наблюдения необходимо включать студентов не только с установленными ФР ССЗ, выявленной артериальной гипертензией, но и измененными показателями ЦГД. В профилактические осмотры необходимо добавить простой метод исследования гемодинамики – компрессионную осциллометрию

Identification of differentially methylated genes in first‑trimester placentas with trisomy 16

The presence of an extra chromosome in the embryo karyotype often dramatically affects the fate of pregnancy. Trisomy 16 is the most common aneuploidy in first-trimester miscarriages. The present study identified changes in DNA methylation in chorionic villi of miscarriages with trisomy 16. Ninety-seven differentially methylated sites in 91 genes were identified (false discovery rate (FDR) 0.15) using DNA methylation arrays. Most of the differentially methylated genes encoded secreted proteins, signaling peptides, and receptors with disulfide bonds. Subsequent analysis using targeted bisulfite massive parallel sequencing showed hypermethylation of the promoters of specific genes in miscarriages with trisomy 16 but not miscarriages with other aneuploidies. Some of the genes were responsible for the development of the placenta and embryo (GATA3-AS1, TRPV6, SCL13A4, and CALCB) and the formation of the mitotic spindle (ANKRD53). Hypermethylation of GATA3-AS1 was associated with reduced expression of GATA3 protein in chorionic villi of miscarriages with trisomy 16. Aberrant hypermethylation of genes may lead to a decrease in expression, impaired trophoblast differentiation and invasion, mitotic disorders, chromosomal mosaicism and karyotype self-correction via trisomy rescue mechanisms