Growth traits in pigs are governed by complex polygenic architectures, with most associated loci residing in non-coding regions that exert substantial influence on economically relevant phenotypes. However, the molecular mechanisms underlying these regulatory elements remain poorly characterized. In this study, a non-coding mutation-designated as NR2C2 recognition motif sequence variation (NRMSV), located 2083 bp upstream of the HMGA1 gene-was identified as a functional modulator of growth traits in a three-generation Eurasian hybrid pig population. NR2C2 is a nuclear receptor implicated in skeletal development and metabolic regulation, while HMGA1 is a key determinant of body size across mammalian species. In embryonic fibroblasts, where NR2C2 is abundantly expressed, the mutant NRMSV suppressed transcriptional activity, functioning as a silencer. In contrast, in bone marrow mesenchymal stem cells, characterized by low NR2C2 expression, the same allele acted as a robust transcriptional enhancer. Knockdown of NR2C2 in embryonic fibroblasts abrogated this repression and restored enhancer activity, confirming the context-dependent, bidirectional regulatory effect of NRMSV on HMGA1 expression. These findings establish the NR2C2-NRMSV-HMGA1 pathway as a novel regulatory mechanism underpinning phenotypic variation in pig growth traits, offering mechanistic insights into mammalian developmental regulation and informing targeted genomic selection for improved productivity in porcine breeding programs.
Xie et al. (Wed,) studied this question.