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A paternal folate deficiency model reveals meiotic prophase I as a metabolic sensing window in the male germline [scRNA-seq]

ABSTRACT: Insufficient paternal folate is associated with impaired sperm quality and adverse pregnancy outcomes, yet the developmental timing at which folate deficiency affects spermatogenesis remains unclear. Folate (vitamin B9) supports one-carbon metabolism and the production of the methyl donor S-adenosylmethionine (SAM), thereby linking nutritional status to chromatin regulation. Using a folate-deficient mouse model, we identify meiotic prophase I as a metabolically vulnerable stage in male germ cell development. Folate deficiency perturbs transcriptional programs during meiosis, with a substantial fraction of down-regulated genes associated with CpG island (CGI) promoters. These promoters are marked by bivalent histone methylation (H3K4me3 and H3K27me3)—two SAM-dependent modifications—during meiosis and emerge as preferential epigenomic targets of folate deficiency. Consistent with this vulnerability, active chromatin marks (H3K4me3 and H3K27ac) are markedly reduced at CGI-associated promoters under folate-deficient conditions. Notably, loci that become over-enriched for H3K4me3 in mature sperm first exhibit depletion of active marks during meiosis, revealing dynamic epigenomic remodeling of CGI-associated chromatin states across spermatogenesis. Together, these findings establish meiotic prophase I as a metabolically sensitive window in the male germline and identify CpG island promoters as primary epigenomic targets of paternal folate deficiency, revealing how paternal nutritional status shapes the epigenetic landscape of the male germline.

ORGANISM(S): Mus musculus

PROVIDER: GSE324233 | GEO | 2026/09/28

REPOSITORIES: GEO

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