Genome-Wide Loci Linked to Non-Obstructive Azoospermia Susceptibility May Be Independent of Reduced Sperm Production in Males with Normozoospermia
BIOLOGY OF REPRODUCTION
Authors: Tu, Wenling; Liu, Yunqiang; Shen, Ying; Yan, Yuanlong; Wang, Xianding; Yang, Dong; Li, Lei; Ma, Yongxin; Tao, Dachang; Zhang, Sizhong; Yang, Yuan
Abstract
Non-obstructive azoospermia (NOA) is a complex, multifactorial disease. Recent genome-wide association studies (GWAS) have identified eight NOA susceptibility loci at genome-wide significance of P < 5.0 x 10(-8) in Han Chinese from southeastern, northern, and central China. To better understand the role of the variants in conferring NOA risk, we selected four GWAS loci (HLA-DRA rs3129878, PRMT6 rs12097821, SOX5 rs10842262, and PEX10 rs2477686) that were reported before 2014 to investigate their association with NOA and their potential effects on sperm production in 1177 Han males from southwest China, including 545 patients with idiopathic NOA and 632 controls with normozoospermia. The results confirmed that the HLA-DRA rs3129878 was an NOA susceptibility locus in the present population. Along with our data, meta-analyses supported the association of the four GWAS-linked loci with NOA, whereas an additive effect of the four loci on NOA susceptibility was not found. Interestingly, the normozoospermic males with the risk genotypes of rs12097821 and rs3129878 + rs10842262 + rs12097821 were observed to have higher total sperm counts relative to non-risk genotypes, suggesting that the risk alleles of the genetic loci may not be via impairing spermatogenic ability to express susceptibility to NOA. These findings may advance our understanding of the role of the NOA susceptibility loci, although the results need to be confirmed in larger samples.
Dissection of functional NF-Y-RFX cooperative interactions on the MHC class II ea promoter
JOURNAL OF MOLECULAR BIOLOGY
Authors: Caretti, G; Cocchiarella, F; Sidoli, C; Villard, J; Peretti, M; Reith, W; Mantovani, R
Abstract
Transcription of major histocompatibility complex (MHC) class II genes depends upon the trimeric complexes RFX and NF-Y binding; to the conserved X-Y promoter elements. We produced and purified the RFX subunits from Escherichia coli, reconstituted DNA-binding to the mouse Ea X box and dissected the interactions with NF-Y. RFX and NF-Y do not interact in solution, but make cooperative interactions in EMSA: a minimal NF-Y, composed of the evolutionary conserved domains, is sufficient and the RFXAP N-terminal half is expendable. Altering the X-Y distance abolishes cooperativity, indicating that DNA imposes severe spatial constraints. When tested on a highly positioned nucleosome, RFX binds DNA well and NF-Y does not increase its affinity further. Transfections of NF-Y subunits, but not RFX, in class II negative cells improves basal transcription and coexpression of the two activators has a synergistic effect, while modestly increasing CIITA-mediated activation. These results show that interactions between the two trimers on DNA are key to MHC class II expression. (C) 2000 Academic Press.