The osteoporosis risk variant rs9820407 at 3p22.1 acts as an allele-specific enhancer to regulates CTNNB1 expression by long-range chromatin loop formation

AbstractBoth Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc) are autoimmune diseases sharing similar genetic backgrounds. Genome-wide association studies (GWASs) have constantly disclosed numerous genetic variants conferring to both disease risks at 7q32.1, but the functional mechanisms underlying them are still largely unknown. Through combining fine-mapping and functional epigenomic analyses, we prioritized a potential independent functional SNP (rs13239597) within TNPO3 promoter region, residing in a putative enhancer element. Functional analysis integrating expression quantitative trait locus (eQTL) and high-throughput chromatin interaction (Hi-C) demonstrated that IRF5 is the distal target gene (~118kb) of rs13239597, which is a key regulator of pathogenic autoantibody dysregulation increased risk of both SLE and SSc. We experimentally validated the long-range chromatin interactions between rs13239597 and IRF5 using chromosome conformation capture (3C) assay. We further demonstrated that rs13239597-A acted as an allele-specific enhancer regulating IRF5 expression, independently of TNPO3 by using dual-luciferase reporter assays and CRISPR-Cas9. Particularly, the transcription factor EVI1 could preferentially bind to rs13239597-A allele and increase the enhancer activity to regulate IRF5 expression. Taken together, our results uncovered the mechanistic insight connecting between a noncoding functional variant with a distal immunologically pathogenic gene IRF5, which might obligate in understanding the complex genetic architectures of SLE and SSc pathogenesis.

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Risk variant in miR-544a binding site in CCDC170 is associated with osteoporosis

10.1101/595918 ◽

2019 ◽

Author(s):

Xinhong Liu ◽

Yang Wang ◽

Qin Tan ◽

Yunqi He ◽

Xin Zhao

Keyword(s):

Mirna Target ◽

Disease Risk ◽

Potential Therapeutic Target ◽

Osteoporosis Therapy ◽

Risk Variant ◽

Genomic Variations ◽

Target Sites ◽

Allele Specific ◽

Specific Regulation ◽

Osteoporosis Risk

AbstractMicroRNAs (miRNAs) play essential roles in regulating bone formation and homeostasis. Genomic variations within miRNA target sites may therefore be important sources of genetic differences in osteoporosis risk. To investigate this possibility, we searched for miRNA recognition sites within genes using the TargetScan, miRNASNP and miRbase databases. In this study, we showed that miR-544a differentially regulated the allele variants of rs6932603 in the CCDC170 3 ′ untranslated (3′-UTR). We also showed that miR-544a suppressed osteogenesis and promoted osteoclastogenesis by regulating the expressions of Runx2, Osterix, Alp, Col1a1, Osteopontin (OPN) ,Osteocalcin (OCN) and Osteoprotegerin (OPG). Our results suggest that allele-specific regulation of CCDC170 by miR-544a explains the observed disease risk, and provides a potential therapeutic target for osteoporosis therapy.

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