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Author(s): Dankang Li [sup.1], Qinglin Zhao [sup.1], Xiaowen Huang [sup.1], Chengda Zhang [sup.2], Opolot Godfrey [sup.1], Weidong Zhang [sup.1] Author Affiliations: (1) Department of Epidemiology, School of Public Health, Zhengzhou [...], Background Folate supplementation treatment is the first-line therapy in hyperhomocysteinaemia (HHcy). Up to 40% of HHcy patients do not benefit from folate therapy. Genetic and epigenetic factors of one-carbon metabolism (1-CM) might be identified as a predictor of folate supplementation treatment response. In the present study, we attempt to identify whether genetic and epigenetic factors might predict folate treatment response. Methods A total of 230 patients with HHcy were involved in this prospective cohort study. Differences between baseline concentrations and concentrations obtained at 90 days of treatment were calculated to evaluate the treatment response. General linear models and Pearson correlation was used to explore associations among single-nucleotide polymorphisms (SNPs), DNA methylation, and folate treatment response. Finally, mediation analysis was performed to investigate whether DNA methylation of MTRR mediates the association between SNPs and treatment response. Results MTHFD rs1950902 and MTRR rs162036, rs1801394 was associated with the folate treatment response (P = 0.000, 0.048, and 0.043, respectively). CBS and CBS_2 DNA methylation was significantly associated with folate treatment response (P = 0.0009 and < 0.001). DNA methylation of MTHFR, MTR, and MTRR was also significantly associated with folate treatment response (P < 0.001). DNA methylation of MTRR and MTRR_1 mediated 40.71% and 40.47% of the effect of rs1801394 on folate treatment response, respectively. Conclusions Our results indicated that the 1-CM gene SNPs and DNA methylation was associated with folate treatment response and can be further evaluated relationship between SNPs and DNA methylation in 1-CM with treatment response in a larger sample.

Introduction Inorganic arsenic (iAs) is the chemical form of As commonly found in drinking water (ATSDR 2007) and in some foods (Cubadda et al. 2017). Chronic exposure to iAs has [...], Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risks of iAs-induced diseases. Mechanisms underlying these diseases have been extensively studied using animal models. However, substantive differences between humans and laboratory animals in efficiency of iAs methylation have hindered the translational potential of the laboratory studies. Objectives: The goal of this study was to determine whether humanization of the As3mt gene confers a human-like pattern of iAs metabolism in mice. Methods: We generated a mouse strain in which the As3mt gene along with the adjacent Borcs7 gene was humanized by syntenic replacement. We compared expression of the mouse As3mt and the human AS3MT and the rate and pattern of iAs metabolism in the wild-type and humanized mice. Results: AS3MT expression in mouse tissues closely modeled that of human and differed substantially from expression of AS3MT. Detoxification of iAs was much less efficient in the humanized mice than in wild-type mice. Profiles for iAs and its methylated metabolites in tissues and excreta of the humanized mice were consistent with those reported in humans. Notably, the humanized mice expressed both the full-length AS3MT that catalyzes iAs methylation and the human-specific [AS3MT.sup.d2d3] splicing variant that has been linked to schizophrenia. Conclusions: These results suggest that AS3MT is the primary genetic locus responsible for the unique pattern of iAs metabolism in humans. Thus, the humanized mouse strain can be used to study the role of iAs methylation in the pathogenesis of iAs-induced diseases, as well as to evaluate the role of [AS3MT.sup.d2d3] in schizophrenia. https://doi.org/10.1289/EHP6943

In Saccharomyces cerevisiae, H3 methylation at lysine 4 (H3K4) is mediated by Set1. Set1 is a large protein bearing a conserved RNA recognition motif in addition to its catalytic C-terminal [...]