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Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients.

ABSTRACT: The role of the host in development of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not well understood. A cohort of prospectively enrolled patients with persistent methicillin-resistant S. aureus bacteremia (PB) and resolving methicillin-resistant S. aureus bacteremia (RB) matched by sex, age, race, hemodialysis status, diabetes mellitus, and presence of implantable medical device was studied to gain insights into this question. One heterozygous g.25498283A > C polymorphism located in the DNMT3A intronic region of chromosome 2p with no impact in messenger RNA (mRNA) expression was more common in RB (21 of 34, 61.8%) than PB (3 of 34, 8.8%) patients (P = 7.8 × 10-6). Patients with MRSA bacteremia and g.25498283A > C genotype exhibited significantly higher levels of methylation in gene-regulatory CpG island regions (?methylation = 4.1%, P < 0.0001) and significantly lower serum levels of interleukin-10 (IL-10) than patients with MRSA bacteremia without DNMT3A mutation (A/C: 9.7038 pg/mL vs. A/A: 52.9898 pg/mL; P = 0.0042). Expression of DNMT3A was significantly suppressed in patients with S. aureus bacteremia and in S. aureus-challenged primary human macrophages. Small interfering RNA (siRNA) silencing of DNMT3A expression in human macrophages caused increased IL-10 response upon S. aureus stimulation. Treating macrophages with methylation inhibitor 5-Aza-2'-deoxycytidine resulted in increased levels of IL-10 when challenged with S. aureus In the murine sepsis model, methylation inhibition increased susceptibility to S. aureus These findings indicate that g.25498283A > C genotype within DNMT3A contributes to increased capacity to resolve MRSA bacteremia, potentially through a mechanism involving increased methylation of gene-regulatory regions and reduced levels of antiinflammatory cytokine IL-10.

SUBMITTER: Mba Medie F

PROVIDER: S-EPMC6778225 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients.

Mba Medie Felix F Sharma-Kuinkel Batu K BK Ruffin Felicia F Chan Liana C LC Rossetti Maura M Chang Yu-Ling YL Park Lawrence P LP Bayer Arnold S AS Filler Scott G SG Ahn Richard R Reed Elaine F EF Gjertson David D Yeaman Michael R MR Fowler Vance G VG

Proceedings of the National Academy of Sciences of the United States of America 20190916 40

The role of the host in development of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not well understood. A cohort of prospectively enrolled patients with persistent methicillin-resistant S. aureus bacteremia (PB) and resolving methicillin-resistant S. aureus bacteremia (RB) matched by sex, age, race, hemodialysis status, diabetes mellitus, and presence of implantable medical device was studied to gain insights into this question. One heterozygo ...[more]

PMID: 31527248

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Project description:BACKGROUND: Improvement of ?-tocopherol content is an important breeding aim to increase the nutritional value of crops. Several efforts have been conducted to improve the ?-tocopherol content in soybean [Glycine max (L.) Merr.] through transgenic technology by overexpressing genes related to ?-tocopherol biosynthesis or through changes to crop management practices. Varieties with high ?-tocopherol content have been identified in soybean germplasms. The heritability of this trait has been characterized in a cross between high ?-tocopherol variety Keszthelyi Aproszemu Sarga (KAS) and low ?-tocopherol variety Ichihime. In this study, the genetic mechanism of the high ?-tocopherol content trait of KAS was elucidated. RESULTS: Through QTL analysis and fine mapping in populations from a cross between KAS and a Japanese variety Ichihime, we identified ?-TMT3, which encodes ?-tocopherol methyltransferase, as a candidate gene responsible for high ?-tocopherol concentration in KAS. Several nucleotide polymorphisms including two nonsynonymous mutations were found in the coding region of ?-TMT3 between Ichihime and KAS, but none of which was responsible for the difference in ?-tocopherol concentration. Therefore, we focused on transcriptional regulation of ?-TMT3 in developing seeds and leaves. An F5 line that was heterozygous for the region containing ?-TMT3 was self-pollinated. From among the progeny, plants that were homozygous at the ?-TMT3 locus were chosen for further evaluation. The expression level of ?-TMT3 was higher both in developing seeds and leaves of plants homozygous for the ?-TMT3 allele from KAS. The higher expression level was closely correlated with high ?-tocopherol content in developing seeds. We generated transgenic Arabidopsis plants harboring GUS gene under the control of ?-TMT3 promoter from KAS or Ichihime. The GUS activity assay showed that the activity of ?-TMT3 promoter from KAS was higher than that of Ichihime. CONCLUSIONS: The genetic variation in ?-TMT3, which plays a major role in determining ?-tocopherol concentration, provides significant information about the regulation of tocopherol biosynthesis in soybean seeds. This knowledge will help breeding programs to develop new soybean varieties with high ?-tocopherol content.

Dataset Information

Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients.

Publications

Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients.

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