Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis

The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs and prevailing osteoporosis-relevant regulatory roles for their chromatin interaction genes. Further motif enrichment and network mapping prioritized several putative, key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected one top-ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underline the roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help to better understand the intricate molecular regulatory mechanisms underlying osteoporosis risk loci. [Display omitted] •Massive report assay detected allelic enhancer activities on 319 osteoporosis GWAS SNPs•477 chromatin-interaction genes were enriched for roles in osteoporosis pathogenesis•Network mapping prioritized key TFs binding to enhancer SNPs controlling osteoporosis•rs11202530-G binds to YY2 to strengthen PAPSS2 expression and osteoblast differentiation Chen et al. combined chromatin interaction conformation profiling and high-throughput reporter assay to survey osteoporosis GWAS SNPs with allelic enhancer activities. They prioritized key TFs controlling osteoporosis binding to enhancer SNPs and divulged a YY2-condensed regulatory axis conferring risk for osteoporosis through modified PAPSS2 expression and osteoblast differentiation.