Faculty Opinions recommendation of Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development.

AbstractThe mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr model and genome-wide differential DNA methylation in the germline of Mtrr mutant maternal grandfathers. We observe that, while epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional changes that correlate with germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos for at least three wildtype generations in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.

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Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker

10.1101/2020.05.21.109256 ◽

2020 ◽

Author(s):

Georgina E.T. Blake ◽

Xiaohui Zhao ◽

Hong wa Yung ◽

Graham J. Burton ◽

Anne C. Ferguson-Smith ◽

...

Keyword(s):

Congenital Malformations ◽

Epigenetic Inheritance ◽

Folate Metabolism ◽

Transgenerational Epigenetic Inheritance ◽

Hypomorphic Mutation ◽

Genome Wide ◽

A Genome ◽

Epigenetic Instability ◽

Transcriptional Memory ◽

Methylation Defects

ABSTRACTThe mechanism behind transgenerational epigenetic inheritance (TEI) is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrrgt hypomorphic mutation results in TEI of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. In this work, we use a genome-wide approach to reveal genetic stability in the Mtrrgt model and epigenome-wide differential DNA methylation in the germline of Mtrr+/gt maternal grandfathers. While epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional memory of germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos at least until the F3 generation in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.

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Transgenerational effects of abnormal folate metabolism on fetal and placental development

Placenta ◽

10.1016/j.placenta.2013.06.268 ◽

2013 ◽

Vol 34 (9) ◽

pp. A90

Author(s):

Nisha Padmanabhan ◽

Wendy Jia ◽

Colleen Geary-Joo ◽

Xuchu Wu ◽

Anne Ferguson-Smith ◽

...

Keyword(s):

Folate Metabolism ◽

Placental Development ◽

Transgenerational Effects

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Genetic predictors for symptoms recurrenсe in coronary artery disease after percutaneous coronary intervention

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/igpp.2017.4.8527 ◽

2017 ◽

pp. 81-86

Author(s):

Г.А. Березовская ◽

Е.С. Клокова ◽

Н.Н. Петрищев

Keyword(s):

Coronary Artery Disease ◽

Percutaneous Coronary Intervention ◽

Coronary Artery ◽

Coronary Intervention ◽

Folate Metabolism ◽

Genotype Distribution ◽

Polymorphic Markers ◽

Percutaneous Coronary ◽

Artery Disease

Гены тромбообразования и фолатного обмена играют важную роль в развитии и прогрессии ишемической болезни сердца (ИБС). Однако о возможной роли полиморфных маркеров в рецидиве ИБС после чрескожного коронарного вмешательства (ЧКВ) известно недостаточно. Цель исследования: Оценить роль генетических факторов системы тромбообразования и фолатного обмена (полиморфных маркеров генов F5, F2, F13A1, PAI1, HPA1, MTHFR, FGB ), в возобновление клиники ИБС после ЧКВ. Методика: Исследование проводили с использованием выборки из 90 больных ИБС в возрасте от 40 до 75 лет: 75 пациентов после планового ЧКВ (60 мужчин и 15 женщин) и 15 лиц после экстренного ЧКВ (12 мужчин и 3 женщины). Молекулярно-генетическое исследование было выполнено с помощью комплекта реагентов «Сердечно-сосудистые заболевания СтрипМетод»® (ViennaLab Diagnostics GmbH, Австрия), выявляющие следующие варианты: F5, F2, F13A1, PAI1, HPA1, MTHFR, FGB . Результаты: В результате исследования была показана ассоциация полиморфного маркера G103T ( Val34Leu ) гена F13A1 (фактор свертываемости крови 13, субъединица A1) с развитием рецидивирующего состояния ИБС после ЧКВ. Выявлены статистически значимые различия в распределении частот генотипов полиморфного маркера Val34Leu гена F13A1 . Показано, что частота генотипа Val/Val у пациентов с осложнениями была выше, чем у пациентов без таковых: 0,700 и 0,400 соответственно (c = 7,78; p = 0,020), при этом генотип Val/Val проявил себя как фактор риска развития осложнений: ОШ = 3,50 (95%ДИ 1,37-8,93). При сравнении аллелей выявили, что частота аллеля L у больных с осложнениями была ниже, чем у лиц без таковых: 0,167 и 0,375 соответственно (p = 0,004), и носительство аллеля L уменьшало вероятность развития осложнений: ОШ = 0,33 (95%ДИ 0,15-0,72). Заключение: Носительство варианта 34V гена F13A1 , кодирующего A-субъединицу фактора свёртывания 13, предрасполагает к возобновлению клинических проявлений ИБС после ЧКВ. Genes of thrombosis and folate metabolism play an important role in development and progression of coronary artery disease (CAD). However, a possible role of polymorphic markers in CAD relapse following percutaneous coronary intervention (PCI) is not sufficiently understood. Background. Reports have indicated an association of genetic factors generally related with thrombophilia and recurrence of symptoms for coronary artery disease (CAD) following a percutaneous coronary intervention (PCI) due to restenosis and in-stent thrombosis. However, the relapse can also be caused by progression of atherosclerosis and endothelial dysfunction in unoperated blood vessels. Aim: To assess the role of genetic risk factors involved in thrombosis and folate metabolism (polymorphic markers of F5, F2, F13A1, PAI1, HPA1, MTHFR, and FGB genes) in recurrence of CAD symptoms after PCI. Methods: The study included 90 patients with CAD aged 40-75; 75 of these patients had undergone elective PCI (60 men and 15 women) and 15 patients - emergency PCI (12 men and 3 women). Molecular genetic tests were performed using a CVD StripAssays® reagent kit (ViennaLab Diagnostics GmbH, Austria) to identify the following genetic variations: F5, F2, F13A1, PAI1, HPA1, MTHFR, and FGB . Results: The study results showed a significant association of the G103T ( Val34Leu ) polymorphism in the F13A1 gene with relapses of IHD after PCI. Significant differences were found in genotype distribution frequencies of the Val34Leu polymorphism in the F13A1 gene. The frequency of Val / Val genotype was higher in patients with complications than without complications, 0.700 and 0.400, respectively (c = 7.78, p = 0.020). Furthermore, the Val/Val genotype can be classified as a risk factor for complications (OR = 3.50; 95% CI, 1.37-8.93). The L allele frequency was lower in patients with complications than in those without complications (0.167 and 0.375, respectively, p = 0.004), and carriage of the L allele reduced the likelihood of complications (OR = 0.33; 95% CI 0.15-0.72). Conclusion: Carriage of the 34V variant in the F13A1 gene that encodes the coagulation factor XIII A subunit predisposes to a relapse of CAD symptoms after PCI.

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