公益財団法人 セコム科学技術振興財団
研究成果報告書

研究課題名「エピゲノム記憶」の概念の確立～生活習慣病の先制医療の実現に向けて～

Establishment of the concept of “epigenome memory”
Towards the realization of preemptive medicine for lifestyle-related diseases

研究期間
平成２８年 ４月 ～ 令和 ２年 ３月

報告年月
令和 ２年 ６月
研究代表者
九州大学 大学院医学研究院 教授
小川 佳宏
Kyushu University, Faculty of Medical Sciences, Professor
Yoshihiro Ogawa

Abstract
Epidemiological and experimental evidence has suggested that nutritional environment in early life isassociated with metabolic diseases in later life, giving rise to the concept of Developmental Origins of Healthand Disease (DOHaD) hypothesis (Science 305: 1733-1736, 2004). We previously demonstrated that
expression of GPAT1 (Gpam), a rate-limiting enzyme of de novo lipogenesis, is enhanced in the mouse
liver during weaning in association with DNA demethylation-dependent recruitment of the lipogenictranscription factor SREBP-1c and ligand-activated PPAR-dependent DNA demethylation regulates thefatty acid -oxidation enzymes in the postnatal mouse liver (Diabetes 61: 2442-2450, 2012; Diabetes 64:775-784, 2015). Epigenetic modifications such as DNA methylation may be involved in many biologicalprocesses, however, the causative effect is unclear.
In this study, we have demonstrated that the fibroblast growth factor-21 gene (Fgf21) is subject
to PPAR-dependent DNA demethylation in the liver during the postnatal period. Reduction in DNA
methylation of Fgf21 can be enhanced via pharmacologic activation of PPAR during the suckling period. We
have also revealed that the DNA methylation status of Fgf21, once established in early life, is relatively
stable and persists into adulthood. Reduced DNA methylation is associated with enhanced induction ofhepatic FGF21 expression after PPAR activation, which may partly explain the attenuation of diet-induced
obesity in adulthood. We propose that DNA methylation of Fgf21 represents a form of epigenetic memory thatpersists into adulthood, and it may have a role in the developmental programming of obesity (Nat. Commun. 9:e636, 2018). However, there is no direct evidence for the effect of site-specific DNA methylation on gene
expression. In this study, we employ the dCas9-SunTag and single-chain variable fragment (scFv)-TET1
catalytic domain (TET1CD) system to induce targeted DNA demethylation of the Fgf21 promoter both in vitro
and in vivo. We have succeeded in targeted DNA demethylation of the Fgf 21 promoter both in Hepa1-6 cells
and in the liver from PPAR-deficient mice, with increased gene expression response to synthetic PPAR ligand
administration and fasting, respectively. This study provides direct evidence that the DNA methylation status of aparticular gene may determine the magnitude of the gene expression response to environmental cues (Sci. Rep. 10:e5181, 2020).
We have also examined the epigenetic memory in other organs outside the liver. We have focused upon DNA
methylation of brain-derived neurotrophic factor gene (Bdnf) exon IV and its expression and their effect onlearning capacity in the offspring derived from dams with thiamazole (MMI)-induced mild maternal
hypothyroxinemia (M offspring) and control offspring (C offspring). We have found that M offspring show an
impaired learning capacity in the behavior test. Hippocampal Bdnf exon IV expression at the basal level iscomparable between M and C offspring. However, it is significantly weaker in M offspring than in C offspring
after the behavior tests. Persistent DNA hypermethylation is also found in the Bdnf exon IV promoter in thehippocampus of M offspring relative to C offspring, which may cause the attenuation of Bdnf exon IV
expression in M offspring. This study provides evidence that mild maternal hypothyroxinemia induces
persistent DNA hypermethylation in Bdnf exon IV in offspring as epigenetic memory, which may result in
long-term cognitive disorders (Thyroid 28: 395-406, 2018).
Collectively, this study has established DNA methylation as a mediator of epigenetic memory,thereby providing the evidence to formulate the guidelines for the nutritional management of women
expected to be pregnant and those who are during pregnancy or lactation.