RESUMEN
Paternal dietary conditions may contribute to metabolic disorders in offspring. We have analyzed the role of the stress-dependent epigenetic regulator cyclic AMP-dependent transcription factor 7 (ATF7) in paternal low-protein diet (pLPD)-induced gene expression changes in mouse liver. Atf7+/- mutations cause an offspring phenotype similar to that caused by pLPD, and the effect of pLPD almost vanished when paternal Atf7+/- mice were used. ATF7 binds to the promoter regions of â¼2,300 genes, including cholesterol biosynthesis-related and tRNA genes in testicular germ cells (TGCs). LPD induces ATF7 phosphorylation by p38 via reactive oxygen species (ROS) in TGCs. This leads to the release of ATF7 and a decrease in histone H3K9 dimethylation (H3K9me2) on its target genes. These epigenetic changes are maintained and induce expression of some tRNA fragments in spermatozoa. These results indicate that LPD-induced and ATF7-dependent epigenetic changes in TGCs play an important role in paternal diet-induced metabolic reprograming in offspring.
Asunto(s)
Factores de Transcripción Activadores/genética , Dieta con Restricción de Proteínas , Epigénesis Genética , Hígado/fisiología , Espermatozoides/fisiología , Factores de Transcripción Activadores/metabolismo , Animales , Femenino , Regulación de la Expresión Génica , Histonas/metabolismo , Lisina/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Mutación , Fosforilación , Regiones Promotoras GenéticasRESUMEN
Various stresses increase disease susceptibility and accelerate aging, and increasing evidence suggests that these effects can be transmitted over generation. Epidemiological studies suggest that stressors experienced by parents affect the longevity of their offspring, possibly by regulating telomere dynamics. Telomeres are elongated by telomerase and shortened by certain stresses as well as telomere repeat-containing RNA (TERRA), a telomere transcript. However, the mechanism underlying the transgenerational effects is poorly understood. Here, we show that TNF-α, which is induced by various psychological stresses, induces the p38-dependent phosphorylation of ATF7, a stress-responsive chromatin regulator, in mouse testicular germ cells. This caused a release of ATF7 from the TERRA gene promoter in the subtelomeric region, which disrupted heterochromatin and induced TERRA. TERRA was transgenerationally transmitted to zygotes via sperm and caused telomere shortening. These results suggest that ATF7 and TERRA play key roles in paternal stress-induced telomere shortening in the offspring.
Asunto(s)
Factores de Transcripción Activadores/genética , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Transcripción Genética , Factor de Necrosis Tumoral alfa/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Animales , Cromatina/genética , Heterocromatina/genética , Humanos , Ratones , Fosforilación , Regiones Promotoras Genéticas , Estrés Psicológico , Telómero/genética , Acortamiento del Telómero/genéticaRESUMEN
Paternal environmental factors can epigenetically influence gene expressions in offspring. We demonstrate that restraint stress, an experimental model for strong psychological stress, to fathers affects the epigenome, transcriptome, and metabolome of offspring in a MEKK1-dATF2 pathway-dependent manner in Drosophila melanogaster. Genes involved in amino acid metabolism are upregulated by paternal restraint stress, while genes involved in glycolysis and the tricarboxylic acid (TCA) cycle are downregulated. The effects of paternal restraint stress are also confirmed by metabolome analysis. dATF-2 is highly expressed in testicular germ cells, and restraint stress also induces p38 activation in the testes. Restraint stress induces Unpaired 3 (Upd3), a Drosophila homolog of Interleukin 6 (IL-6). Moreover, paternal overexpression of upd3 in somatic cells disrupts heterochromatin in offspring but not in offspring from dATF-2 mutant fathers. These results indicate that paternal restraint stress affects metabolism in offspring via inheritance of dATF-2-dependent epigenetic changes.
Asunto(s)
Factor de Transcripción Activador 2/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiología , Epigenoma , Células Germinativas/fisiología , Metaboloma , Transcriptoma , Factor de Transcripción Activador 2/metabolismo , Animales , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Padre , Quinasa 1 de Quinasa de Quinasa MAP/fisiología , Masculino , Transducción de Señal/fisiologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Increasing evidence indicates that parental diet affects the metabolism and health of offspring. It is reported that paternal low-protein diet (pLPD) induces glucose intolerance and the expression of genes involved in cholesterol biosynthesis in mouse offspring liver. The aim of the present study was to determine the effect of a pLPD on gene expression in offspring white adipose tissue (WAT), another important tissue for the regulation of metabolism. RNA-seq analysis indicated that pLPD up- and down-regulated 54 and 274 genes, respectively, in offspring WAT. The mRNA expression of many genes involved in lipogenesis was down-regulated by pLPD feeding, which may contribute to metabolic disorder. The expression of carbohydrate response element-binding protein ß (ChREBP-ß), an important lipogenic transcription factor, was also significantly lower in the WAT of pLPD offspring, which may have mediated the down-regulation of the lipogenic genes. By contrast, the LPD did not affect the expression of lipogenic genes in the WAT of the male progenitor, but increased the expression of lipid oxidation genes, suggesting that a LPD may reduce lipogenesis using different mechanisms in parents and offspring. These findings add to our understanding of how paternal diet can regulate metabolism in their offspring.