Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood

Yuan, Xunmei; Tsujimoto, Kazutaka; Hashimoto, Kazuhito; Kawahori, Kenichi; Hanzawa, Nozomi; Hamaguchi, Miho; Seki, Takami; Nawa, Makiko; Ehara, Tatsuya; Kitamura, Yohei; Hatada, Izuho; Konishi, Morichika; Itoh, Nobuyuki; Nakagawa, Yoshimi; Shimano, Hitoshi; Toda, Takako; Kamei, Yasutomi; Ogawa, Yoshihiro

doi:10.1038/s41467-018-03038-w

Cited by 69 publications

(72 citation statements)

References 55 publications

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“…5a). Moreover, in our previous report 4 , we found that enhanced DNA demethylation via ligand-activated PPARα specifically occurs at CpG sites in the gene body of Fgf21 in the perinatal mouse liver, and DNA demethylation of these CpG sites was correlated with the induction of gene expression. Taken together, these data suggest that DNA methylation of the gene body of Fgf21 exerts repressive effects on gene expression.…”

Section: Discussionmentioning

confidence: 58%

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Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Hanzawa

Hashimoto

Yuan

et al. 2020

Sci Rep

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Recently, we reported ppARα-dependent DNA demethylation of the Fgf21 promoter in the postnatal mouse liver, where reduced DnA methylation is associated with enhanced gene expression after ppARα activation. However, there is no direct evidence for the effect of site-specific DNA methylation on gene expression. We employed the dCas9-SunTag and single-chain variable fragment (scFv)-TET1 catalytic domain (TET1CD) system to induce targeted DnA methylation of the Fgf21 promoter both in vitro and in vivo. We succeeded in targeted DnA demethylation of the Fgf 21 promoter both in Hepa1-6 cells and PPARα-deficient mice, with increased gene expression response to ppARα synthetic ligand administration and fasting, respectively. this study provides direct evidence that the DnA methylation status of a particular gene may determine the magnitude of the gene expression response to activation cues. In mammalian cells, DNA methylation is a major epigenetic modification, which regulates gene expression without alteration of the DNA sequence and thus plays a pivotal role in a myriad of physiological and pathological processes, including cell development and differentiation, genome imprinting, and tumorigenesis 1. We reported previously that the DNA methylation status of hepatic metabolic genes dynamically changes in early life, especially during the suckling period, thereby sequentially developing metabolic function in the liver to adapt to the drastic changes in the major nutrition source 2-4. Peroxisome proliferator-activated receptor-α (PPARα) is a nuclear receptor and a key regulator of hepatic lipid metabolism, which is activated by milk lipids as ligands at the onset of lactation. PPARα governs the transcription of major hepatic metabolism-related genes, and the activation of PPARα physiologically leads to DNA demethylation of fatty acid β-oxidation genes in the postnatal mouse liver 3,4. Of note, administration of a synthetic PPARα ligand to mouse dams during the perinatal period induced enhanced reduction of DNA methylation of PPARα target genes in the offspring liver, suggesting that the DNA methylation status of PPARα target genes can be modulated with ease during the perinatal period 3,4. A genome-wide analysis of DNA methylation revealed that a few PPARα target genes undergo ligand-activated, PPARα-dependent DNA demethylation during the perinatal period, and the DNA hypomethylation status of these persists into adulthood. Among these genes, which may be referred to as "epigenetic memory genes," we focused on fibroblast growth factor 21 (FGF21), which is a metabolic hormone derived from the liver and a master regulator of glucose and lipid metabolism 5-7 .

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Section: Discussionmentioning

confidence: 58%

“…In silico searches identified 21 CpG sites around the transcription start site (TSS) of Fgf21 (Fig. 1b) 4,17 . We sought cell lines in which the Fgf21 promoter was highly DNA methylated.…”

Section: Resultsmentioning

confidence: 99%

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Hanzawa

Hashimoto

Yuan

et al. 2020

Sci Rep

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“…A total of 267 blood samples were obtained from healthy, unrelated adult female Xinong Saanen dairy goats, which were reared on the Chinese native dairy goat breeding farm in Qianyang County, Shaanxi, China (Zhao et al, 2013). The data regarding the average milk yield (AMY; kg) were obtained directly from the breeding farm, whereas the data regarding the average milk density (AMD) were measured by our study team using a MilkoScan FT120 (FOSS Corporation, Denmark) instrument (Lan et al, 2013b;Zhao et al, 2013). The relevant measurements of these two milk traits are listed in Table 1.…”

Section: Animals Phenotypic Data Recording and Group Classificationmentioning

confidence: 99%

“…Notably, PITX1 has been characterized as an activator of the POMC gene and a partner of Pit1 causing differential expression of GH, PRL, and TSH, and thereby affecting milk performance in animals (Carvalho et al, 2006). In 2013, both the PITX1 gene and another PITX family member, PITX2, were identified as being associated with milk performance in dairy goats (Lan et al, 2013b;Zhao et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

DNA methylation pattern of the goat <i>PITX1</i> gene and its effects on milk performance

Zhao

Zhang

et al. 2019

Arch. Anim. Breed.

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Abstract. Paired-like homeodomain transcription factor 1 (PITX1) is a pivotal gene in the hypothalamic–pituitary–adrenal axis, which is a well-known pathway affecting lactation performance. The aim of this study was to analyze the DNA methylation profile of the PITX1 gene and its relevance to milk performance in Xinong Saanen dairy goats; thus, potential epigenetic markers of lactation performance were identified. A total of 267 goat blood samples were divided into “low” and “high” groups according to two milk traits: the average milk yield (AMY) and the average milk density (AMD). One CpG island in the 3′-flanking region of the PITX1 gene was identified as being related to milk performance. Fisher's exact test demonstrated that the methylation rates of the overall CpG island and the 3rd and 12th CpG-dinucleotide loci in the blood were significantly associated with the AMY, and the overall methylation rate of the high AMY group was relative hypomethylation compared with the low AMY group. The overall methylation rates of this CpG island in mammary gland tissue from dry and lactation periods again exhibited a significant difference: the lactation period showed relative hypomethylation compared with the dry period. Bioinformatic transcription factor binding site prediction identified some lactation performance related transcription factors in this CpG island, such as CTCF, STAT, SMAD, CDEF, SP1, and KLFS. Briefly, overall methylation changes of the CpG island in the PITX1 gene are relevant to lactation performance, which will be valuable for future studies and epigenetic marker-assisted selection (eMAS) in the breeding of goats with respect to lactation performance.

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“…These adaptive DNA methylation changes may benefit the lipid metabolism of the infants in later life, as indicated by the human studies on the breastfeeding and children’s metabolism diseases [72]. In line with the human studies, animal models have shown that the adaptive demethylation of FGF21 (fibroblast growth factor 21, involved in lipid metabolism) and enhanced expression are persistent into adulthood, resulting in attenuation of diet-induced obesity of adults [73]. Another well known study in an animal model is that of the viable yellow agouti mouse, which examined the effects of maternal dietary genistein on the decreasing Agouti gene expression through increasing the methylation levels of a retrotransposable element in the promoter of the Agouti gene.…”

Section: Epigenetic Adaptation: Positive Effectsmentioning

confidence: 99%

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

Tian

Marsit

2018

Curr Epidemiol Rep

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Purpose of Review Epigenetic processes represent important mechanisms underlying developmental plasticity in response to environmental exposures. The current review discusses three classes of environmentally-induced epigenetic changes reflecting two aspects of that plasticity, toxicity effects as well as adaptation in the process of development. Recent findings Due to innate resilience, epigenetic changes caused by environmental exposures may not always lead impairments but may allow the organisms to achieve positive developmental outcomes through appropriate adaptation and a buffering response. Thus, some epigenetic adaptive responses to an immediate stimulus or exposure early in life would be expected to have a survival advantage but these same responses may also result in adverse developmental outcomes as they persists into later life stage. Although accumulating literature has identified environmentally induced epigenetic changes and linked them to health outcomes, we currently face challenges in the interpretation of the functional impact of their epigenetic plasticity. Summary Current environmental epigenetic research suggest that epigenetic processes may serve as a mechanism for resilience, and that they can be considered in terms of their impact on toxicity as a negative outcome, but also on adaptation for improved survival or health. This review encourages epigenetic environmental studies to move deeper inside into the functional meaning of epigenetic plasticity in the development.

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Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood

Cited by 69 publications

References 55 publications

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

DNA methylation pattern of the goat <i>PITX1</i> gene and its effects on milk performance

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

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Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood

Cited by 69 publications

References 55 publications

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

DNA methylation pattern of the goat &lt;i&gt;PITX1&lt;/i&gt; gene and its effects on milk performance

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

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DNA methylation pattern of the goat <i>PITX1</i> gene and its effects on milk performance