Genetic information is transmitted to the offspring and greatly contributes 63to their phenotype and disease susceptibility. However, it is not the sole determinant. For example, in type 2 diabetes, which is a hereditary disease, genome-wide association studies revealed that genetic variants can account for only ~30% of the heritability. Cohort studies of adopted children demonstrated that the contribution of the growth environment to the heritability of type 2 di-abetes is also limited. These facts suggest the existence of yet-to-be-determined heritable mechanisms and suggest that the non-genetic bases of heredity need to be considered as a potential cause of hereditary diseases.Accumulating evidence has demonstrated that epigenetic memory is also transmitted across generations in various organisms. To reveal non-genetic bases of disease heritability, our lab is studying epigenetic inheritance mecha-nisms in mammalian embryos. Our specific aims are as follows (Figure): (1) To understand the molecular basis and functions of epigenetic establishment and inheritance during gametogenesis and embryogenesis. (2) To understand the link between epigenetic inheritance and the pre- and peri-conceptional paren-tal environment; (3) To understand how the parental environment can affect disease susceptibility in the offspring. To address these questions, we integrate cutting-edge low-input epigenome analysis technologies, reproductive engi-neering techniques and various genome/epigenome-modified mouse models. Our study will call for an evaluation of the contribution of epigenetic mecha-nisms to hereditary diseases and provide a foundation for establishing new ap-proaches for preventive and predictive medicine.Figure: Parental programming hypothesis. Parental epigenomes are established during gametogenesis, and some of them are inherited by embryos to regulate gene expres-sion in the fetus and placenta. Our lab investigates the effect of the pre-/peri-conceptional parental environ-ment on epigenetic inheritance and disease predisposi-tion in the offspring.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. Nat Genet 53, 539-550 (2021)Invited presentationsInoue A. “Maternal epigenetic inheritance by Polycomb repressive complexes” EMBO meeting CellBio Virtual 2021 (USA/Online) December 2021Inoue A. “Developmental regulation by maternal in-heritance of histone modifications” Research Seminar at Institute for Molecular and Cellular Regulation (Gunma, Japan) November 2021Inoue A. “Maternal epigenetic inheritance by Polycomb repressive complexes” KALAS International Symposium 2021 (Korea/Online) July 2021Inoue A. “Transgenerational inheritance of histone modifications in mammals” The 1380th Biology Seminar at the University of Tokyo (Tokyo/Online) May 2021.Inoue A. “Maternal epigenetic inheritance by Polycomb repressive complexes” The 10th symposium of Smart Aging Research Center at Tohoku University (Miyagi, Japan/Online) May 2021YCI Laboratory for Metabolic EpigeneticsYoung Chief Investigator: Azusa Inoue
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