Authors
Xi Cheng, Cuipei Wu, Xiaohe Yang, Rui Liu
Published in
Human molecular genetics. Volume 35. Issue 14. Jun 06, 2026.
Abstract
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.
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.
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).
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.
PMID:
42447329
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.
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