AUTHOR=Cao Can-hui , Wei Ye , Liu Rang , Lin Xin-ran , Luo Jia-qi , Zhang Qiu-ju , Lin Shou-ren , Geng Lan , Ye Si-kang , Shi Yu , Xia Xi 

TITLE=Three-Dimensional Genome Interactions Identify Potential Adipocyte Metabolism-Associated Gene STON1 and Immune-Correlated Gene FSHR at the rs13405728 Locus in Polycystic Ovary Syndrome

JOURNAL=Frontiers in Endocrinology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.686054

DOI=10.3389/fendo.2021.686054

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>rs13405728 was identified as one of the most prevalent susceptibility loci for polycystic ovary syndrome (PCOS) in Han Chinese and Caucasian women. However, the target genes and potential mechanisms of the rs13405728 locus remain to be determined.</p></sec><sec><title>Methods</title><p>Three-dimensional (3D) genome interactions from the ovary tissue were characterized <italic>via</italic> high-through chromosome conformation capture (Hi-C) and Capture Hi-C technologies to identify putative targets at the rs13405728 locus. Combined analyses of eQTL, RNA-Seq, DNase-Seq, ChIP-Seq, and sing-cell sequencing were performed to explore the molecular roles of these target genes in PCOS. PCOS-like mice were applied to verify the expression patterns.</p></sec><sec><title>Results</title><p>Generally, <italic>STON1</italic> and <italic>FSHR</italic> were identified as potential targets of the rs13405728 locus in 3D genomic interactions with epigenomic regulatory peaks, with <italic>STON1</italic> (<italic>P</italic>=0.0423) and <italic>FSHR</italic> (<italic>P</italic>=0.0013) being highly expressed in PCOS patients. <italic>STON1</italic> co-expressed genes were associated with metabolic processes (<italic>P</italic>=0.0008) in adipocytes (<italic>P</italic>=0.0001), which was validated in the fat tissue (<italic>P</italic>&lt;0.0001) and ovary (<italic>P</italic>=0.0035) from fat-diet mice. The immune system process (GO:0002376) was enriched in <italic>FSHR</italic> co-expressed genes (<italic>P</italic>=0.0002) and PCOS patients (<italic>P</italic>=0.0002), with <italic>CD4</italic> high expression in PCOS patients (<italic>P</italic>=0.0316) and PCOS-like models (<italic>P</italic>=0.0079). Meanwhile, <italic>FSHR</italic> expression was positively correlated with <italic>CD4</italic> expression in PCOS patients (P=0.0252) and PCOS-like models (<italic>P</italic>=0.0178). Furthermore, androgen receptor (<italic>AR</italic>) was identified as the common transcription factor for <italic>STON1</italic> and <italic>FSHR</italic> and positively correlated with the expression of <italic>STON1</italic> (<italic>P</italic>=0.039) and <italic>FSHR</italic> (<italic>P</italic>=4e-06) in ovary tissues and PCOS-like mice.</p></sec><sec><title>Conclusion</title><p>Overall, we identified <italic>STON1</italic> and <italic>FSHR</italic> as potential targets for the rs13405728 locus and their roles in the processes of adipocyte metabolism and <italic>CD4</italic> immune expression in PCOS, which provides 3D genomic insight into the pathogenesis of PCOS.</p></sec>