Integrative high-throughput enhancer surveying and functional verifying divulges YY2 condensed regulatory axis conferring risk for osteoporosis
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ABSTRACT:
PROVIDER: PRJNA970258 | ENA |
REPOSITORIES: ENA
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Project description:The precise roles of chromatin organizations at osteoporosis risk loci remains 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 SNPs. We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) which 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 interacted genes. Further motif enrichment and network mapping prioritized several putative key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected on 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 underlined roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help better understand the intricate molecular regulatory mechanisms underlying osteoporosis-risk loci.
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Project description: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.
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