つくばリポジトリ NC 9 636

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Epi genet i c modul at i on of Fgf 21 i n t he per i nat al mouse l i ver amel i or at es di et -i nduced obesi t y i n adul t hood 著者 j our nal or publ i cat i on t i t l e vol ume page r ange year 権利 URL Yuan Xunmei ,Tsuj i mot o Kazut aka, Hashi mot o Koshi ,Kawahor i Keni chi ,Hanzawa Nozomi ,Hamaguchi Mi ho, Seki Takami ,Nawa Maki ko, Ehar a Tat suya, Ki t amur a Yohei ,Hat ada I zuho, Koni shi Mor i chi ka, I t oh Nobuyuki ,Nakagawa Yoshi mi ,Shi mano Hi t oshi ,Takai -I gar ashi Takako, Kamei Yasut omi ,Ogawa Yoshi hi r o Nat ur e communi cat i ons 9 636 2018- 02 (C) The Aut hor (s) 2018 Thi s ar t i cl e i s l i censed under a Cr eat i ve Commons At t r i but i on 4. 0 I nt er nat i onal Li cense, whi ch per mi t s use, shar i ng, adapt at i on, di st r i but i on and r epr oduct i on i n any medi um or f or mat ,as l ong as you gi ve appr opr i at e cr edi t t o t he or i gi nal aut hor (s) and t he sour ce, pr ovi de a l i nk t o t he Cr eat i ve Commons l i cense, and i ndi cat e i f changes wer e made. The i mages or ot her t hi r d par t y mat er i al i n t hi s ar t i cl e ar e i ncl uded i n t he ar t i cl e ’s Cr eat i ve Commons l i cense, unl ess i ndi cat ed ot her wi se i n a cr edi t l i ne t o t he mat er i al .I f mat er i al i s not i ncl uded i n t he ar t i cl e ’s Cr eat i ve Commons l i cense and your i nt ended use i s not per mi t t ed by st at ut or y r egul at i on or exceeds t he per mi t t ed use, you wi l l need t o obt ai n per mi ssi on di r ect l y f r om t he copyr i ght hol der .To vi ew a copy of t hi s l i cense, vi si t ht t p: cr eat i vecommons. or g/ l i censes/ by/ 4. 0/ ht t p: hdl .handl e. net /2241/ 00151179 doi: 10.1038/s41467-018-03038-w Cr eat i ve Commons :表示 ht t p: cr eat i vecommons. or g/ l i censes/ by/ 3. 0/ deed. j a ARTICLE DOI: 10.1038/s41467-018-03038-w OPEN 1234567890()Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood Xunmei Yuan1,14, Kazutaka Tsujimoto1, Koshi Hashimoto2, Kenichi Kawahori1, Nozomi Hanzawa1, Miho Hamaguchi1,14, Takami Seki1, Makiko Nawa3, Tatsuya Ehara1,4, Yohei Kitamura4, Izuho Hatada5, Morichika Konishi6, Nobuyuki Itoh7, Yoshimi Nakagawa 8,9, Hitoshi Shimano8,9, Takako Takai-Igarashi10, Yasutomi Kamei11 &Yoshihiro Ogawa1,12,13,14 The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferatoractivated receptor (PPAR) α–dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARα during the suckling period. We also reveal 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 of hepatic FGF21 expression after PPARα activation, which may partly explain the attenuation of diet-induced obesity in adulthood. We propose that Fgf21 methylation represents a form of epigenetic memory that persists into adulthood, and it may have a role in the developmental programming of obesity. 1 Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. of Preemptive Medicine and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. 3 Laboratory of Cytometry and Proteome Research, Nanken-Kyoten and Research Core Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. 4 Wellness and Nutrition Science Institute, Morinaga Milk Industry Co.,Ltd, 5-183, Higashihara, Zama, Kanagawa 252-8583, Japan. 5 Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan. 6 Department of Microbial Chemistry, Kobe Pharmaceutical University, 1-19-4, Motoyama-kitamachi, Higashinada-ku, Kobe, Hyogo 658-8558, Japan. 7 Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. 8 Department of Internal Medicine (Metabolism and Endocrinology),Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan. 9 International Institute for Integrative Sleep Medicine (WPI-IIIS),University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan. 10 Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan. 11 Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, 1-5 Hangi-cho, Shimogamo, Sakyo-ku, Kyoto 606-8522, Japan. 12 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 13 Japan Agency for Medical Research and Development, CREST, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan. 14Present address: Department of Molecular and Cellular Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Xunmei Yuan and Kazutaka Tsujimoto contributed equally to this work. Correspondence and requests for materials should be addressed to K.H. email: khashimoto.mem@tmd.ac.jp) or to Y.O. email: yogawa@intmed3.med.kyushu-u.ac.jp) 2 Department NATURE COMMUNICATIONS |2018)9:636 DOI: 10.1038/s41467-018-03038-w |www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS |DOI: 10.1038/s41467-018-03038-w N utritional experiences in early life have a long-lasting influence on the development of body weight, thus affecting the risk of obesity in later life1,2. For instance, malnutrition in early life as a result of poor nutrition during pregnancy and/or the lactation period may be stored onto the offspring genome as memory. It may persist into adulthood, thereby increasing the susceptibility to metabolic diseases such as obesity in later life, which has been referred to as developmental programming or the “developmental origins of health and disease (DOHaD)”hypothesis1,3,4. Epigenetic modifications represent a prime candidate mechanism to explain the long-lasting influence on metabolic phenotypes such as obesity5. Indeed, a considerable amount of evidence has recently been accumulated regarding the role of epigenetic dysregulation in human obesity6–8. The methylation of cytosine residues in CpG dinucleotides (i.e.,cytosine followed by guanine) or DNA methylation is a major epigenetic modification known to suppress gene transcription. Cell type-specific patterns of CpG methylation are mitotically inherited, as well as highly stable in differentiated cells and tissues9–11. Accordingly, most epigenetic studies concerning the developmental programming of obesity focused on DNA methylation. However, whether DNA methylation status of a particular gene, when established in early life, can influence the developmental programming of obesity is currently unknown. On the contrary, we previously reported that DNA methylation status of metabolic genes in the liver dynamically changes in early life, even during the suckling period, thus sequentially activating hepatic metabolic function to adapt to the nutritional environment12,13. In the previous report, we found that upon the onset of lactation after birth, milk serves as a ligand to activate the nuclear receptor peroxisome proliferator-activated receptor (PPAR)α, which is a key transcriptional regulator of hepatic lipid metabolism mediating the adaptive response to energy store13,14,15. PPARα activation via milk lipid ligands physiologically leads to DNA demethylation of fatty-acid β-oxidation genes in the postnatal mouse liver13. Given that PPARα may act as a sensor of milk lipids during the suckling period16,17, it is likely that PPARα-dependent DNA demethylation primes the activation of the fatty-acid β-oxidation pathway in the liver, thereby contributing to the efficient production of energy from milk lipids. We also demonstrated that administration of a synthetic PPARα ligand to mouse dams during the perinatal period induces enhanced reductions in DNA methylation of fatty-acid β-oxidation genes in the liver of the offspring, suggesting that DNA methylation status of hepatic metabolism-related genes can be modulated via ligand-activated PPARα during the perinatal period. Therefore, these findings prompted us to explore whether DNA methylation status of PPARα target genes, which is modulated and established in a PPARα-dependent manner in early life, persists into adulthood, and if so, we sought to clarify how these changes influence adult metabolic phenotypes such as obesity. Using a genome-wide analysis of DNA methylation, we identified a few PPARα target genes that underwent ligand-activated PPARα-dependent DNA demethylation during the perinatal period and whose DNA hypomethylation status persists into adulthood. Among these genes, which can be referred to as epigenetic memory genes, we focused on fibroblast growth factor 21 (FGF21),a bona fide PPARα target gene, which is a major hepatocyte-derived hormone implicated in the regulation of energy homeostasis and body weight through its effect on multiple target organs including adipose tissue18–20. In this study, we provide the first evidence that the PPARαdependent Fgf21 demethylation occurs in the postnatal mouse 2 NATURE COMMUNICATIONS |2018)9:636 liver. Importantly, Fgf21 methylation status can be modulated in early life, and once established it persists into adulthood and exerts long-term effects on the magnitude of gene expression response to environmental cues, which may account in part for the attenuation of diet-induced obesity. Results Genome-wide analysis of PPARα-dependent DNA demethylation. In a previous study, we found that maternal administration of a synthetic PPARα ligand (Wy 14643, Wy) during the perinatal period induces enhanced reductions in DNA methylation of fatty-acid β-oxidation genes in the postnatal mouse liver13. We employed the microarray-based integrated analysis of methylation by isoschizomers (MIAMI)21 to analyze genome-wide DNA methylation status in the livers of offspring derived from damsadministered Wy dissolved in dimethyl sulfoxide (DMSO) as vehicle (Veh) during the late gestation (from 14 to 18 days after fertilization: e14–18) and lactation periods (from 2 to 16 days after birth: D2–D16) Fig. 1a).Accordingly, we sought to identify the genes for which DNA hypomethylation status induced via ligand-activated PPARα in the perinatal mouse liver persists into adulthood. To clarify whether Wy was transferred to pups via the breast milk, we analyzed gastric contents, which mainly consisted of the milk derived from dams, in offspring at D16 using mass spectrometry (liquid chromatography/tandem mass spectrometry [LC/MS-MS])As shown in Supplementary Fig. 1, LC/MS-MS detected the same precursor (mass-to-charge ratio [m/z],324.06] and product peaks (m/z, 306.04) in both a standard sample consisting of purified Wy and milk samples from Wy-offspring (derived from Wy-treated dams),suggesting that Wy is present in the breast milk of dams (Supplementary Fig. 1).We performed lipid composition analysis of milk using the offspring gastric contents by gas chromatography (GC).GC showed no significant difference in lipid composition of milk between Wy- and Veh-offspring (derived from Veh-treated dams),suggesting that Wy administration to dams during the lactation period did not affect milk lipid composition (Supplementary Table 1).MIAMI analysis revealed that more genes were DNA hypomethylated in Wy-offspring relative to Veh-offspring at D16 (Fig. 1b),and were DNA hypermethylated at 14W (14W) Fig. 1c).A correlation plot showing the differences at D16 (xaxis) vs. 14W (y-axis) indicates a weak but significant correlation between DNA methylation status at D16 and 14W (Fig. 1d).We found that 424 genes were DNA hypomethylated in Wy-offspring relative to Veh-offspring at D16, and 33 genes were DNA hypomethylated at 14W after birth (Fig. 1e).Consequently, we identified 25 genes, which were DNA hypomethylated in Wyoffspring relative to Veh-offspring both at D16 and 14W (Fig. 1e).Pathway analysis of the 25 genes yielded the PPAR signaling pathway among which 11 genes are known to be PPARα target genes15 (Table 1).PPARα-dependent Fgf21 demethylation in the suckling period. Among the 11 aforementioned PPARα target genes, we focused on FGF21, a peptide hormone which plays a critical role in regulating energy homeostasis20. To verify whether Fgf21 demethylation physiologically occurs in a PPARα-dependent manner, we examined Fgf21 methylation status in PPARα-deficient (PPARαKO) and wild-type (WT) offspring via bisulfite-sequencing analysis. In silico search identified 21 CpG sites around the transcription start site (TSS) of Fgf21, with two PPAR response elements (PPRE1 and PPRE2) that are located approximately 1000 and 100 bp upstream of the TSS, respectively (Fig. 2a)22. DOI: 10.1038/s41467-018-03038-w |www.nature.com/naturecommunications ARTICLE NATURE COMMUNICATIONS |DOI: 10.1038/s41467-018-03038-w a Gestation Adulthood Lactation Offspring Veh-offspring Wy-offspring e0 e14 e18 D2 D16 10W 14W Wy14643 Dam b 4W c D16 14W 0.5 2.0 1.0 1.0 0.4 Msp i signal difference (log10 Cy3/Cy5) Msp i signal difference (log10 Cy3/Cy5) 0.6 0.5 Hpa II signal difference (log10 Cy3/Cy5) d 1.0 1.0 Hpa II signal difference (log10 Cy3/Cy5) e 3.0 r =0.232 p

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