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Transgenerational effects of prenatal restricted diet on gene expression and histone modifications in the rat.

ABSTRACT: Dietary triggers acting on a developing fetus can affect the functioning of the body in later life; this can be observed on various levels, including epigenetic modifications and gene expression. Early-life programmed changes may be transmitted to successive generations. In this study, the impact of prenatal restricted diet was studied in four generations of rats. We hypothesized that this diet can induce changes in the expression of major genes involved in two epigenetic mechanisms: DNA methylation and histone modifications. The transcript level of six genes involved in these processes (Dnmt1, Dnmt3a, Dnmt3b, Mecp2, Hdac1, and Sin3a) was therefore determined in three tissues (liver, adipose, and muscle). This diet was found to have no effect on the F0 pregnant females. In the F1 progeny (fetuses at day 19 of pregnancy and 4-week-old rats) significant differences in the expression of the genes were observed mostly in the liver; in subsequent generations, we therefore studied only this tissue. Among the genes encoding DNA methyltransferases, significant changes were observed for Dnmt1 in the F1 animals from the restricted group, but these were no longer evident in F2 and F3. The Dnmt3a and Dnmt3b genes showed no differences in mRNA level in F1 fetuses. Concerning the transcript level of the Mecp2 gene only in F1 generation significant changes were found. For the histone modification genes, an increase in the expression of Hdac1 in fetus liver was found in F1 and F2, while its level decreased in F3. The abundance of the Sin3a transcript varied in all generations. It was also found that the mRNA levels of the studied genes correlated highly positive with each other, but only in fetuses from the F1 restricted group. The DNA methylation cell potential, defined as the ratio of SAM (S-adenosylmethionine) to SAH (S-adenosylhomocysteine), was measured in the liver, with no alterations being found in the restricted groups. Evaluation of global histone H3 acetylation showed that it underwent a significant increase in the fetal livers of F1, while during aging (four-week old animals) this difference was no longer maintained. A tendency of increased H3 acetylation in fetuses was also detected in F2 generation. In F1 fetuses from restricted group the increased H3 acetylation positively correlated with transcriptional status of the studied genes. Our results indicate that the prenatal restriction diet can affect the activity of genes involved in epigenetic mechanisms in the liver across generations. Moreover, this feeding type influenced the global histone H3 acetylation in fetal liver.

SUBMITTER: Nowacka-Woszuk J

PROVIDER: S-EPMC5825138 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Transgenerational effects of prenatal restricted diet on gene expression and histone modifications in the rat.

Nowacka-Woszuk Joanna J Szczerbal Izabela I Malinowska Anna M AM Chmurzynska Agata A

PloS one 20180223 2

Dietary triggers acting on a developing fetus can affect the functioning of the body in later life; this can be observed on various levels, including epigenetic modifications and gene expression. Early-life programmed changes may be transmitted to successive generations. In this study, the impact of prenatal restricted diet was studied in four generations of rats. We hypothesized that this diet can induce changes in the expression of major genes involved in two epigenetic mechanisms: DNA methyla ...[more]

PMID: 29474484

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Project description:The nutritional factors acting during early life can affect the development of the organism. It has been hypothesized that such programmed traits can be inherited by later generations. In this work, we present for the first time the effect of food deprivation in pregnant dams and its consequences for the transcription and DNA methylation profiles in the offspring of the next three generations. We used a 50% reduction in dietary intake during pregnancy in the rat and determined whether this altered the hepatic DNA methylation and transcription levels in female fetuses over three generations. Targeted next-generation sequencing (tNGS) was used in the first generation for 1748 genes associated with six selected biological processes. The selected cytosines were then studied by pyrosequencing in F1-F3. The transcript level of the selected genes was determined by the real-time PCR. The tNGS approach indicated 394 cytosines, in close proximity to 374 genes, with a statistically significant difference in methylation levels between the control and restricted groups. A gene clustering analysis revealed 23 molecular pathways to which the studied genes were assigned. Only seven cytosines were differently methylated to more than 10%, and so these sites were studied next using pyrosequencing. The observation from NGS was confirmed for only one cytosine located near the St6galnac5 gene, though this was with the opposite effect. A difference was also observed for the Usp30 gene, though in proximity to the cytosine selected from NGS. In F3, the differences were observed for the Oxct2b gene. We also found differences in methylation levels between generations for the Grb10 and St6galnac5 genes, but independently of the diet used. The transcript levels of selected genes (Usp30, Grb10, Pld1, St6galnac5, Oxct2b, Khk, and Acsl4) were not altered in F1, while changes were detected for Pld1 and Oxct2b in F2 and F3, respectively. Prenatal food deprivation did not induce broad changes in hepatic DNA methylation of the genes involved in lipid or carbohydrate metabolism, and did not result in alterations in their transcription. Thus, the hypothesis that transgenerational inheritance is induced by dietary restriction was not confirmed.

Project description:BackgroundHistone Mark Modifications (HMs) are crucial actors in gene regulation, as they actively remodel chromatin to modulate transcriptional activity: aberrant combinatorial patterns of HMs have been connected with several diseases, including cancer. HMs are, however, reversible modifications: understanding their role in disease would allow the design of 'epigenetic drugs' for specific, non-invasive treatments. Standard statistical techniques were not entirely successful in extracting representative features from raw HM signals over gene locations. On the other hand, deep learning approaches allow for effective automatic feature extraction, but at the expense of model interpretation.ResultsHere, we propose ShallowChrome, a novel computational pipeline to model transcriptional regulation via HMs in both an accurate and interpretable way. We attain state-of-the-art results on the binary classification of gene transcriptional states over 56 cell-types from the REMC database, largely outperforming recent deep learning approaches. We interpret our models by extracting insightful gene-specific regulative patterns, and we analyse them for the specific case of the PAX5 gene over three differentiated blood cell lines. Finally, we compare the patterns we obtained with the characteristic emission patterns of ChromHMM, and show that ShallowChrome is able to coherently rank groups of chromatin states w.r.t. their transcriptional activity.ConclusionsIn this work we demonstrate that it is possible to model HM-modulated gene expression regulation in a highly accurate, yet interpretable way. Our feature extraction algorithm leverages on data downstream the identification of enriched regions to retrieve gene-wise, statistically significant and dynamically located features for each HM. These features are highly predictive of gene transcriptional state, and allow for accurate modeling by computationally efficient logistic regression models. These models allow a direct inspection and a rigorous interpretation, helping to formulate quantifiable hypotheses.

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Transgenerational effects of prenatal restricted diet on gene expression and histone modifications in the rat.

Publications

Transgenerational effects of prenatal restricted diet on gene expression and histone modifications in the rat.

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