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A novel class of tRNA-derived small non-coding RNAs in response to myocardial hypertrophy and contribute to intergenerational inheritance

ABSTRACT: tRNA-derived fragments (tRFs) have served as new class of non-coding RNA and played important role in regulating cellular RNA processing and protein translation, which was also proved have function on the intergenerational effects of paternal disease. However, there was no study reported the influence of tRFs on myocardial hypertrophy. In the current study, we explore the hypothesis that tRFs in response to myocardial hypertrophy and contribute to intergenerational inheritance.We used isoproterenol induced myocardial hypertrophy rat model. Small RNA (< 40 nt) tanscriptome sequencing was used to select differential expressed tRFs. We over-expressed the highest foldchange tRFs on H9c2 cell to check its function in enlarging cardiocytes surface area. We also compared the tRFs expression pattern in F0 sperm and F1 offspring heart between myocardial hypertrophy (Hyp) and control group (Con), as well as evaluated the phynotype of myocardial hypertrophy in F1 offspring. ISO successfully induced a typical cardiac hypertrophy model in our study. Small RNA-seq revealed tRFs were extremely enriched (84%) in Hyp heart. Overexpression tRFs1 and tRFs2 would both enlarge the surface area of cardiac cell and increase hypertrophic markers (ANF, BNP, and β-MHC) expression. tRFs1, tRFs2, tRFs3 and tRFs4 were also significantly high expressed in Hyp F0 sperm and in Hyp F1 offspring heart, but no function of tRFs7, tRFs9 and tRFs10. Compared to Con F1 offspring, Hyp F1 offspring had high expression levels of β-MHC and ANP genes, and increased fibrosis levles and apoptotic cell in heart.We demonstrate that tRFs are involved in regulating the response of myocardial hypertrophy, it might serve as novel epigenetic factor and contribute to intergenerational inheritance of cardiac hypertrophy.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE106511 | GEO | 2017/11/04

SECONDARY ACCESSION(S): PRJNA417069

REPOSITORIES: GEO

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Project description:The global prevalence of obesity is increasing across age and gender. The rising burden of obesity in young people contributes to the early emergence of type 2 diabetes. Having one parent obese is an independent risk factor for childhood obesity. While the detrimental impact of diet-induced maternal obesity on offspring is well established, the extent of the contribution of obese fathers is unclear, as is the role of non-genetic factors in the casual pathway. Here we show that paternal high fat diet exposure programmed Î²-cell âdysfunctionâ in their F1 female offspring. Chronic high fat diet consumption in Sprague Dawley fathers led to increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had lower body weight at day-1, increased pubertal growth rate, impaired insulin secretion and glucose tolerance, in the absence of obesity or increased adiposity. Paternal high fat diet was observed to alter gene expression of pancreatic islet genes in adult female offspring (P < 0.001); affected functional clusters includes calcium ion binding, insulin, apoptosis, Wnt and cell cycle organ/system development. This is the first reported study in mammals describing non-genetic, intergenerational transmission of metabolic sequelae of high fat diet from father to offspring. These findings support a role of fathers in metabolic programming of offspring and form a framework for further studies. F0 founders were male Sprague Dawley rats, divided into two groups, high fat (HF) and control. The HF fathers were given commercially prepared high-fat pellets (43% as fat); while the controls ate standard laboratory chow (9% as fat). The two groups of fathers had distinct phenotype; the HF fathers were significantly heavier with increased adiposity, they were also glucose intolerant and insulin resistant. At 15 weeks of age, fathers were mated with normal females consuming chow, to generate the F1 offspring. Only female offspring were studied. Female offspring were weaned unto standard laboratory chow at 3 weeks. At 6 and 12 weeks, intraperitoneal glucose tolerance test (IpGTT) was performed to measure blood glucose and insulin profile; at 11 weeks, intraperitoneal insulin tolerance test was done. The body weight and adiposity of these offspring were not different between the two groups. The HF offspring had glucose intolerance and impaired glucose-induced insulin response, mainly at the acute phase, observed since 6 weeks. The IpITT was not different between groups. At 13 weeks, islets were harvested from the two groups of offspring.

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A novel class of tRNA-derived small non-coding RNAs in response to myocardial hypertrophy and contribute to intergenerational inheritance

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