etycoOauroMObesity is a growing social problem in the modern world and the obese Pcgf1/6 2-cellMorulaH3K27me3CTRKOH3K27me3 lossCTRmatKOInheritanceWT placentaSperm (wild-type)Pcgf1/6 KOoocytematernal KOOocyte2-cellH3K27me3PlacentaWTPcgf1/6 matKOSpongiotrophoblast layerPcgf1/6 matKO placenta60Vicious cycle of obesityvia EPIGENOMEMaternalobesityHigher risk of obesityABlInheritance of the loss-of-H3K27me3 stateEpigenetic changes in oocytesLoss of placental imprinting, Placental enlargementpopulation has been increasing worldwide. Since obesity is associated with an increased risk of various diseases, including cancer, infertility, heart diseases, and type 2 diabetes (T2D), and greatly impacts national healthcare costs, development of preventive medicine and treatment for metabolic syn-dromes has been long awaited. Recently, intergenerational heritability of T2D has received much attention. Genetic variants and mutations are estimated to account for <30% of T2D heritability, suggesting the existence of a non-genetic inheritance mechanism. Studies in animal models have suggested that gametes, at least in part, mediate the inheritance. While significant progress has recently been made in understanding the mechanisms of sperm-mediated paternal in-heritance, almost nothing is known about the mechanisms of oocyte-mediated maternal inheritance.Our lab is studying how maternal metabolic disorders are inherited by the next generation via epigenetic mechanisms. Our specific aims are as follows: (1) To understand the molecular basis and functions of maternal epigenetic inheritance (Figure); (2) To understand whether and how maternal metabolic disorders could alter the epigenomes of oocytes, early embryos and offspring. We integrate low-input epigenome analysis technologies and reproductive engi-neering techniques to address these questions. Our studies will not only reveal the mechanisms of intergenerational epigenetic inheritance in mammals but also provide a foundation for establishing new approaches to prevent inheri-tance of metabolic disorders.Figure: Aims and research tools of the Metabolic Epigenetics YCI Lab(A) Illustration of a hypothetical model showing ma-ternal inheritance of metabolic disorders via the oocyte epigenome. (B) Evidence that a region-specific loss of H3K27me3 state in oocytes is irreversibly inherited by embryos. This causes loss of imprinting in the placenta and placental enlargement.Recent Major PublicationsMei H, Kozuka C, Hayashi R, Kumon M, Koseki H, Inoue A. H2AK119ub1 guides maternal inheritance and zygotic deposition of H3K27me3 in mouse embryos. Nature Genetics 53, 539-550 (2021)Chen Z, Yin Q, Inoue A, Zhang C, Zhang Y. Allelic H3K27me3 to allelic DNA methylation switch maintains noncanonical imprinting in extraembryonic cells. Sci Adv 5, eaay7246 (2019)Shishikura K, Kuroha S, Matsueda S, Iseki H, Matsui T, Inoue A, Arita M. Acyl-CoA synthetase 6 regulates long-chain polyunsaturated fatty acid composition of mem-brane phospholipids in spermatids and supports normal spermatogenic processes in mice. FASEB J 33, 14194-203 (2019)Invited presentationsInoue A. “Maternal epigenetic inheritance by PRC1-PRC2 crosstalk” The RIKEN-Helmholtz Zentrum Munchen joint epigenetics seminar (Online) October 2020Inoue A. “Maternal epigenetic inheritance ~perspectives from animal cloning~” The 113th Society for Reproduc-tion and Development meeting (Online) September 2020Inoue A. “Variant PRC1-mediated H2A mono-ubiqui-tination ensures maternal inheritance of H3K27me3” The 93rd annual meeting of the Japanese biochemical society (Online) September 2020Inoue A. “Variant PRC1-mediated H2A mono-ubiquitina-tion ensures maternal inheritance of H3K27me3” Re-search seminar at Gregor Mendel Institute of Molecular Plant Biology GmbH (Vienna, Austria/Online) May 2020Inoue A. “Intergenerational epigenetic inheritance in mammals” Lecture at CiRA retreat 2019 (Shiga, Japan) February 2020YCI Laboratory for Metabolic EpigeneticsYoung Chief Investigator: Azusa Inoue
元のページ ../index.html#66