Several recent studies have suggested that epigenetic changes induced by the environment can be inherited through the germline from the parent to the progeny. For example, a high fat paternal diet in rodents changes the insulin and glucose levels in serum of the offspring and induces an abnormal response after glucose or insulin injections. Though phenotypic changes have been found in the offspring, the mechanisms remain largely unclear. We hypothesized that the fat content of a diet may have an impact on chromatin composition during gamete development and this may have the potential to influence the reprogramming process that takes place during the transition from spermatogonia to spermatids. Using an obesity mouse model, we examined treatment of high versus low fat diet in C57BL/6J male mice and its effect on H3 retention in spermatozoa and examined mRNA expression of several fat synthesis related genes in the liver of offspring. In order to address molecular mechanisms of how diet induced effects may possibly be transferred to the next generation, we examined the chromatin of diet treated fathers. We first addressed the question of whether CG methylation is altered in spermatozoa at differentially methylated regions (DMR) of genomic imprinted genes. Using bisulfite sequencing we examined CG methylation at seven known ICRs (Imprinting Control Region) which show complete CG methylation in sperm or are excluded from CG methylation in sperm. The patterns did not reveal significant methylation differences comparing genomic DNA derived from HFD to LFD fathers. Although most of the histone proteins are replaced by protamines during spermatogenesis, about 1-5% of histones are retained in sperm and can shuttle to the progeny. To address the effect of diet on histone content in sperm, we performed chromatin immunoprecipitation (ChIP) of sperm using specific antibodies against histone H3 followed by high-throughput sequencing. We observed greater H3 enrichment in sperm of high fat diet parents compared to low fat diet parents, indicating enhanced H3 retention during sperm generation after high fat diet treatment. The genes with the highest H3 enrichment at their promoter region are involved in the regulation of embryogenesis. Furthermore, we performed ChIP-Seq for the H3K4me1 modification in sperm and found specific retention of H3K4me1in high fat samples at a discrete subset of genes that encode for embryonic transcriptional regulators. Finally, we examined mRNA of 20 selected genes that play a role in fatty acid metabolism and the oxidative stress response in the liver of offspring. We found seven (out of 20) genes were differentially expressed in high fat diet progeny compared to low fat diet progeny including MT1, MT2, Fasn, Por and Acaca. Obesity is associated with a number of human diseases including diabetes, cardiovascular diseases, cancer and arthritis. Obesity is in part induced by dietary choices. Our study suggests that high fat dietary exposure in an animal model can modulate histone composition at regulatory genes implicated in developmental processes. Furthermore, high fat dietary exposure of the parent can modulate the gene expression profile in the progeny.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010014-21
Application #
9343572
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Ren, Jianke; Hathaway, Nathaniel A; Crabtree, Gerald R et al. (2018) Tethering of Lsh at the Oct4 locus promotes gene repression associated with epigenetic changes. Epigenetics 13:173-181
Han, Yixing; Ren, Jianke; Lee, Eunice et al. (2017) Lsh/HELLS regulates self-renewal/proliferation of neural stem/progenitor cells. Sci Rep 7:1136
He, Xiaozhen; Yan, Bin; Liu, Shuang et al. (2016) Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase. Cancer Res 76:5743-5755
Han, Yixing; Gao, Shouguo; Muegge, Kathrin et al. (2015) Advanced Applications of RNA Sequencing and Challenges. Bioinform Biol Insights 9:29-46
Jiang, Y; Yan, B; Lai, W et al. (2015) Repression of Hox genes by LMP1 in nasopharyngeal carcinoma and modulation of glycolytic pathway genes by HoxC8. Oncogene 34:6079-91
Ren, Jianke; Briones, Victorino; Barbour, Samantha et al. (2015) The ATP binding site of the chromatin remodeling homolog Lsh is required for nucleosome density and de novo DNA methylation at repeat sequences. Nucleic Acids Res 43:1444-55
Terashima, Minoru; Barbour, Samantha; Ren, Jianke et al. (2015) Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression. Epigenetics 10:861-71
Lungu, Cristiana; Muegge, Kathrin; Jeltsch, Albert et al. (2015) An ATPase-deficient variant of the SNF2 family member HELLS shows altered dynamics at pericentromeric heterochromatin. J Mol Biol 427:1903-15
Yu, Weishi; McIntosh, Carl; Lister, Ryan et al. (2014) Genome-wide DNA methylation patterns in LSH mutant reveals de-repression of repeat elements and redundant epigenetic silencing pathways. Genome Res 24:1613-23
Yu, Weishi; Briones, Victorino; Lister, Ryan et al. (2014) CG hypomethylation in Lsh-/- mouse embryonic fibroblasts is associated with de novo H3K4me1 formation and altered cellular plasticity. Proc Natl Acad Sci U S A 111:5890-5

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