Epitranscriptomic Alteration and Planar Cell Polarity Signaling In Diabetic Embroyopathy

糖尿病胚胎病中的表观转录组改变和平面细胞极性信号传导

• 批准号: 10676158
• 负责人: E. Albert Reece
• 金额: $ 57.52万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676158
• 关键词: Age; American; Animal Model; Antibodies; Apoptosis; Binding; Biological Process; Cell Differentiation process; Cell Polarity; Cell Proliferation; Child; Congenital Abnormality; DNA; Defect; Development; Diabetes Mellitus; Dominant-Negative Mutation; Embryo; Embryonic Development; Epigenetic Process; Exposure to; FOXO3A gene; Functional disorder; Gene Deletion; Gene Expression; Genes; Genetic Recombination; Genetic Transcription; Glucose; Heterozygote; Immunoprecipitation; Incidence; JUN gene; LoxP-flanked allele; MAPK8 gene; Mediating; Messenger RNA; Methylation; Methyltransferase; Modernization; Modification; Movement; Neural Tube Closure; Neural Tube Defects; Neuroepithelial Cells; Neurons; Oxidative Stress; Pathogenesis; Pathway interactions; Phosphotransferases; Physiological; Preconception Care; Pregnancy in Diabetics; Prevention strategy; RNA; RNA methylation; Repression; Role; Severities; Signal Transduction; Teratogens; Testing; Transgenic Model; Transgenic Organisms; Woman; diabetic; diabetic embryopathy; embryo culture; epitranscriptomics; improved; inhibitor; insight; mRNA Expression; maternal diabetes; mouse model; neuroepithelium; novel; offspring; overexpression; planar cell polarity; receptor; reproductive; response; superoxide dismutase 1; transcription factor; transcriptome sequencing; transgene expression

Pregestational diabetes induces neural tube defects (NTDs) in the offspring. Even under the best preconception care, women having diabetes are still three- to four-times more likely to have a child with a birth defect than women without diabetes. Mechanistic studies provide important insights for the development of novel prevention strategies. Studies using diabetic embryopathy have revealed the critical involvement of epigenetic modifications in the pathogenesis of NTDs. RNA modifications are involved in important biological processes including development. We observed epitranscriptomic changes in neurulation stage embryos exposed to maternal diabetes. Maternal diabetes decreased the expression of the m6A RNA methylation writer’s methyltransferase- like 3 (METTL3) and METTL14 and altered planar cell polarity. Therefore, we hypothesize that maternal diabetes reduces m6A RNA methylation levels by repressing METTL3 and METTL14 expression through oxidative stress responsive kinase signaling in neurulation stage embryos leading to NTDs, and that restoring METTL3 and METTL14 expression in the developing neuroepithelium ameliorates diabetic embryopathy, whereas deleting either one enhances diabetes induced NTDs. Diabetes-induced RNA hypomethylation alters RNA expression encoding the planar cell polarity (PCP) components resulting in neuroepithelial cell polarity defects and cellular dysfunction. Aim 1 will determine the mechanism underlying maternal diabetes reduced METTL3 and METTL14 expression in the developing embryo. We will examine that two transcription factors c-Jun and FOxO3a, which are downstream of the oxidative stress- activated kinase signaling, act in concert in response to maternal diabetes to suppress METTL3 and METTL14 expression in the developing embryos leading to the reduction of m6A RNA methylation in the neuroepithelium. Aim 2 will investigate the critical role of reduced METTL3 and METTL14 expression in the induction of diabetic embryopathy. Our working hypothesis is that restoring either METLL3 or METTL14 in the developing neuroepithelium rescues m6A RNA methylation and ameliorates diabetic embryopathy. Aim 3 will determine whether reduced m6A RNA methylation dysregulates PCP gene expression leading to neuroepithelial cell polarity defects in diabetic embryopathy. We will determine whether maternal diabetes-induced RNA hypomethylation dysregulates PCP mRNA expression leading to disruption of neuroepithelial cell polarity. We will examine whether maternal diabetes increases Fzd5 expression through repressing METLL3 or METTL14.

妊娠前糖尿病可导致子代神经管缺陷（NTDs）。即使在最好的孕前护理下，患有糖尿病的妇女仍然比没有糖尿病的妇女有三到四倍的可能性生一个有出生缺陷的孩子。机制研究为开发新型预防策略提供了重要见解。利用糖尿病胚胎病的研究揭示了NTD发病机制中表观遗传修饰的重要参与。RNA修饰参与重要的生物学过程，包括发育。我们观察了暴露于母体糖尿病的神经胚形成期胚胎的epitranscriptomic变化。母亲糖尿病降低了m6 A RNA甲基化写入者的甲基转移酶样3（MIL 3）和MIL 14的表达，并改变了平面细胞极性。因此，我们假设母体糖尿病通过抑制神经胚形成期胚胎中的氧化应激反应激酶信号传导抑制胃L3和胃L14表达来降低m6 A RNA甲基化水平，从而导致NTD，并且在发育中的神经上皮中恢复胃L3和胃L14表达可改善糖尿病胚胎病，而缺失其中任何一种可增强糖尿病诱导的NTD。糖尿病诱导的RNA低甲基化改变了编码平面细胞极性（PCP）组分的RNA表达，导致神经上皮细胞极性缺陷和细胞功能障碍。目的1将确定母体糖尿病降低发育中胚胎中胃L3和胃L14表达的潜在机制。我们将研究两种转录因子c-Jun和FOxO 3a，它们是氧化应激激活的激酶信号传导的下游，在对母体糖尿病的反应中协同作用，以抑制发育中的胚胎中的胃L3和胃L14表达，从而导致神经上皮中m6 A RNA甲基化的减少。目的2研究胃L3和胃L14表达降低在糖尿病胚胎病诱导中的关键作用。我们的工作假设是，在发育中的神经上皮中恢复METLL 3或胃L14挽救了m6 A RNA甲基化并改善了糖尿病胚胎病。目的3将确定是否减少m6 A RNA甲基化失调PCP基因表达，导致神经上皮细胞极性缺陷糖尿病胚胎病。我们将确定母体糖尿病诱导的RNA低甲基化是否会导致PCP mRNA表达失调，从而导致神经上皮细胞极性的破坏。我们将研究母体糖尿病是否通过抑制METLL 3或胃L14来增加Fzd 5的表达。

项目成果

RNA Hypomethylation and Unchanged DNA Methylation Levels in the Cortex of ApoE4 Carriers and Alzheimer's Disease Subjects.

ApoE4 携带者和阿尔茨海默病受试者皮质中的 RNA 低甲基化和未改变的 DNA 甲基化水平。

• DOI: 10.2174/1567205019666220831125142
• 发表时间: 2022
• 期刊: Current Alzheimer research
• 影响因子: 2.1
• 作者: Shen,Wei-Bin;Yang,JamesJiao;Yang,Peixin
• 通讯作者: Yang,Peixin