Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring

•Postnatal paternal folate deficiency alters sperm H3K4me3 at developmental loci•Sperm aberrations are retained in the embryo & associated with birth defects•Deregulated gene expression is concordant alterations•Folate KDM1A transgenics enhances levels and defects A father’s lifestyle impacts offspring health; yet, underlying molecular mechanisms remain elusive. We hypothesized that a diet changes methyl donor availability will alter epigenomes to impact embryonic development. Here, we demonstrate folate-deficient (FD) histone H3 lysine 4 trimethylation (H3K4me3) genes putative enhancers. subset of alterations pre-implantation deregulated expression. Using genetic mouse model which sires have pre-existing altered H3K4me2/3 sperm, show FD exacerbates expression, leading an increase defect severity. These findings imply transmitted influences It further suggests epigenetic errors can accumulate worsen outcomes. 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Feeding comparison WT males fed diet. cumulative greater perturbation severity abnormalities offspring. suggest environmentally influenced phenotypes next generation raises possibility several stresses epigenome. C57BL/6J FS, (2.0 mg/kg) FD, (0.3 post 3 weeks age (Figure 1A). After 9–11 spanning two cycles bred female regular chow Pregnancy assessed day E18.5 (Figures S1A S1B). sired litters significantly variability compared FS (F test, p < 0.05; Figure S1A). Post-implantation losses 0.05 comparisons; Skeletal analysis in-depth characterization 1B–1Q). spectrum WT, TG, (Mann-Whitney’s U-test, 0.001 versus 0.0001 TG; Figures 1B–1Q S1C). Malformations included crooked sternebrae unfused cartilage, asymmetrical bones, bent ribs 1D, 1I, 1J, 1K). fetuses had 1C, 1F, 1G, 1K, 1N, 1Q, ranged craniofacial missing bones under-ossified skulls 1F 1G), spinal deformed misplaced vertebrae extra transverse 1N 1Q). shows similar Scholar), postnatally also skeletal loss. Furthermore, demonstrates feeding already augmented generation. understand if there diet-induced could observed high-quality ChIP-seq libraries each experimental group (n = per group; S2). On average, 97% reads aligned genome, yielding approximately 35 sample, 24 mapped uniquely (Table S1). normalized counts H3K4me3-enriched correct library size, composition bias, batch obtained correlation 0.98 replicates S2B). Comparing existing published datasets indicates approach yielded superior signal broad narrow peaks S3; Table S1) Jung 2017Jung Y.H. Sauria M.E.G. Lyu Cheema M.S. Ausio Taylor Corces V.G. states correlate landscapes.Cell 18: 1366-1382Abstract (125) sequencing depth improved ability detect differences H3K4me3. sensitive weaning, 2). Principal component marked clear segregation principal 1 (PC1), being major source 2A, PERMANOVA, permutation-based 0.01; n 1,000 permutations). capture focused top 5% (PC1) determined directionality 2B). Of 1,434 regions, 650 (t 2Biii, 2C, 2E) 784 0.0001; 2Biv, 2D, 2E). different location distributions (Fisher 0.001, 2F 2G). Whereas predominantly located less kb annotated transcriptional start sites (TSS, Fisher 2F), primarily 10 away TSS intergenic Certain studies mostly lack whereas others mainly distal CpG density (Carone 2014Carone Hung J.H. Hainer Chou M.T. Carone D.M. Weng Fazzio T.G. Rando O.J. High-resolution mapping packaging sperm.Dev. Cell. 30: 11-22Abstract (146) Yamaguchi 2018Yamaguchi Hada Fukuda Makino Katou Shirahige Re-evaluating localization sperm-retained modification-dependent accumulation specific regions.Cell 3920-3932Abstract (42) Our S4A–S4D). defined local minima respective curves (CpG threshold 0.478; S4A S4D). Sites preferential (hypergeometric 0.0001), those areas S4B). All moderate highest unaltered Taken together, landscape reprogramming, gain functional insight regards diet-affected