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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #397297

Research Project: Impact of Maternal Influence and Early Dietary Factors on Child Growth, Development, and Metabolic Health

Location: Arkansas Children's Nutrition Center

Title: Maternal high-fat diet modifies epigenetic marks H3K27me3 and H3K27ac in bone to regulate offspring osteoblastogenesis in mice epigenetics

Author
item CHEN, JIN-RAN - Arkansas Children'S Nutrition Research Center (ACNC)
item CAVINESS, PERRY - Arkansas Children'S Nutrition Research Center (ACNC)
item ZHOA, HAIJJUN - Arkansas Children'S Nutrition Research Center (ACNC)
item BELCHER, BEAU - Arkansas Children'S Nutrition Research Center (ACNC)
item WANKADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - University Of Colorado
item BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)
item LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/5/2022
Publication Date: 8/17/2022
Citation: Chen, J., Caviness, P.C., Zhoa, H., Belcher, B., Wankade, U.D., Shankar, K., Blackburn, M.L., Lazarenko, O.P. 2022. Maternal high-fat diet modifies epigenetic marks H3K27me3 and H3K27ac in bone to regulate offspring osteoblastogenesis in mice epigenetics. Epigenetics. https://doi.org/10.1080/15592294.2022.2111759.
DOI: https://doi.org/10.1080/15592294.2022.2111759

Interpretive Summary: Studies have shown that a diet high in fat for a mother during pregnancy can result in significantly lowered bone quality for a child after birth and affect them well into adulthood. Previous data shows that a high fat diet modifies the DNA of genes responsible for bone formation, via DNA methylation and histone modifications, and that Ezh2 is the protein responsible for these modifications. Ezh2, regulates gene expression through addition of a repressive trimethyl group to histones, proteins used to organize DNA. In pre-osteoblasts from mouse embryo it was shown that a maternal high fat diet led to a significant increase of the H3K27me3 epigenetic mark (from Ezh2) and this mark was found primarily in genes responsible for bone formation. In addition to this, pre-osteoblasts from mouse embryo and bone samples from offspring had an increase in H3K27ac marks, which is known to lead to increased gene expression, primarily for osteoblast inhibitor genes. These findings provide a mechanism by which a maternal diet high in fat can control offspring bone development.

Technical Abstract: Studies from both humans and animal models indicated that maternal chronic poor-quality diet, especially a high fat diet (HFD), is significantly associated with reduced bone density and childhood fractures in offspring. When previously studied in a rat model, our data suggested that maternal HFD changes epigenetic marks such as DNA methylation and histone modifications to control osteoblast metabolism. In mouse embryonic and postnatal offspring bone samples, a ChIP-sequencing (ChIP-Seq)-based genome-wide method was used to locate the repressive histone mark H3K27me3 (mediated via the polycomb histone methyltransferase, Ezh2) and expressive histone mark H3K27ac (p300/CBP mediated) throughout the genome. Using isolated mouse embryonic cells from foetal calvaria (osteoblast-like cells), H3K27me3 ChIP-Seq showed that 147 gene bodies and 26 gene promoters in HFD embryotic samples had a greater than twofold increase in H3K27me peaks compared to controls. Among the HFD samples, Pthlh and Col2a1 that are important genes playing roles during chondro- and osteogenesis had significantly enriched levels of H3K27me3. Their decreased mRNA expression was confirmed by real-time PCR and standard ChIP analysis, indicating a strong association with Ezh2 mediated H3K27me3 epigenetic changes. Using embryonic calvaria osteoblastic cells and offspring bone samples, H3K27ac ChIP-Seq analysis showed that osteoblast inhibitor genes Tnfaip3 and Twist1 had significantly enriched peaks of H3K27ac in HFD samples compared to controls. Their increased gene expression and association with H3K27ac were also confirmed by real-time PCR and standard ChIP analysis. These findings indicate that chronic maternal HFD changes histone trimethylation and acetylation epigenetic marks to regulate expression of genes controlling osteoblastogenesis.