Fetal myogenesis chromatin state and CpG from the open alliance markers and their intersection with adult muscle and gastrointestinal genetics.

Abstract

Background: Epigenetic inheritance links fetal chromatin organization and CpG methylation to lifelong tissue phenotypes. We tested the Fetal Chromatin-CpG Developmental Blueprint (FCCD-B) model, proposing that fetal chromatin states shaped by maternal nutrient and transcription factor networks establish regulatory programs preserved in adult traits.

Methods: We integrated 21 970 fetal single-cell transcriptomes with chromatin accessibility data, including 130 myogenic cells. Adult GWAS datasets included 1614 appendicular lean mass (ALM) loci and 445 grip strength loci. Fine-mapping, colocalization, and gene regulatory networks were inferred using GRNBoost2, Enformer, and Basenji, alongside virtual-cell simulations of nutrient and stress perturbations.

Results: ALM and grip strength showed strong genetic correlation (rg = 0.49; Z = 26). Fine-mapping identified 1355 high-confidence ALM loci (median PIP = 0.91). A total of 2935 shared GWAS-eQTL variants overlapped fetal chromatin, with 70-88% accessibility preserved in endothelial and cardiomyocyte lineages. A SMAD3-centered TGF-β network (50 targets) was identified. Simulations showed that vitamin D, folate, and oxidative stress increased myofibril index (+0.141), epithelial regeneration (+0.035), and combined effects (+0.147).

Conclusion: Persistent fetal chromatin and CpG architectures encode regulatory programs linking maternal environment to adult phenotypes, supporting the FCCD-B model as a predictive framework for developmental epigenetics.