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Studies of the H60a locus in C57BL/6 and 129/Sv mouse strains identify the H60a 3'UTR as a regulator of H60a expression.

ABSTRACT: The minor histocompatibility antigen 60 (H60a) is expressed in BALB/C and 129/Sv but not in C57BL/6 strains of mice. We recently found that IFN? down-regulates H60a, but the mechanism of regulation is not known. To better understand the regulation of H60a, we examined the genomic locus of H60a in 129/Sv and C57BL/6 strains. We found that the upstream regulatory region of H60a was present and functional in both strains. Interestingly, IFN? can down-regulate H60a transcripts in cell lines from 129/Sv but not C57BL/6 strains of mice, suggesting that IFN?-dependent regulation of H60a proceeds through cis elements other than the conserved promoter region. We determined that the regulation of H60a by IFN? proceeds through the 3'UTR of H60a, which is present in 129/Sv, but not C57BL/6 cells. We also found that the H60a 3'UTR and microRNAs can contribute to the level of constitutive expression of H60a in tumor cell lines. We conclude that in 129/Sv strain mice, H60a can be regulated by its 3'UTR through IFN? and unknown microRNAs. Since H60a mediates NK cell target recognition, our studies identify a cis element that can regulate virus and tumor surveillance.

SUBMITTER: Zhang H

PROVIDER: S-EPMC3030190 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Studies of the H60a locus in C57BL/6 and 129/Sv mouse strains identify the H60a 3'UTR as a regulator of H60a expression.

Zhang Hui H Hardamon Chanae C Sagoe Bright B Ngolab Jennifer J Bui Jack D JD

Molecular immunology 20101119 4

The minor histocompatibility antigen 60 (H60a) is expressed in BALB/C and 129/Sv but not in C57BL/6 strains of mice. We recently found that IFNγ down-regulates H60a, but the mechanism of regulation is not known. To better understand the regulation of H60a, we examined the genomic locus of H60a in 129/Sv and C57BL/6 strains. We found that the upstream regulatory region of H60a was present and functional in both strains. Interestingly, IFNγ can down-regulate H60a transcripts in cell lines from 129 ...[more]

PMID: 21093919

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Project description:Background: Infections cause the production of inflammatory cytokines such as Interferon gamma (IFNγ). IFNγ in turn prompts the upregulation of a range of host defence proteins including members of the family of guanylate binding proteins (Gbps). In humans and mice alike, GBPs restrict the intracellular replication of invasive microbes and promote inflammation. To study the physiological functions of Gbp family members, the most commonly chosen in vivo models are mice harbouring loss-of-function mutations in either individual Gbp genes or the entire Gbp gene cluster on mouse chromosome 3. Individual Gbp deletion strains differ in their design, as some strains exist on a pure C57BL/6 genetic background, while other strains contain a 129-derived genetic interval encompassing the Gbp gene cluster on an otherwise C57BL/6 genetic background. Methods: To determine whether the presence of 129 alleles of paralogous Gbps could influence the phenotypes of 129-congenic Gbp-deficient strains, we studied the expression of Gbps in both C57BL/6J and 129/Sv mice following in vivo stimulation with adjuvants and after infection with either Toxoplasma gondii or Shigella flexneri. Results: We show that C57BL/6J relative to 129/Sv mice display moderately elevated expression of Gbp2, but more prominently, are also defective for Gbp2b (formerly Gbp1) mRNA induction upon immune priming. Notably, Toxoplasma infections induce robust Gbp2b protein expression in both strains of mice, suggestive of a Toxoplasma-activated mechanism driving Gbp2b protein translation. We further find that the higher expression of Gbp2b mRNA in 129/Sv mice correlates with a gene duplication event at the Gbp2b locus resulting in two copies of the Gbp2b gene on the haploid genome of the 129/Sv strain. Conclusions: Our findings demonstrate functional differences between 129 and C57BL/6 Gbp alleles which need to be considered in the design and interpretation of studies utilizing mouse models, particularly for phenotypes influenced by Gbp2 or Gbp2b expression.

Project description:BackgroundIn the recent years, the use of Doppler-echocardiography has become a standard non-invasive technique in the analysis of cardiac malformations in genetically modified mice. Therefore, normal values have to be established for the most commonly used inbred strains in whose genetic background those mutations are generated. Here we provide reference values for transthoracic echocardiography measurements in juvenile (3 weeks) and adult (8 weeks) 129/Sv mice.MethodsEchocardiographic measurements were performed using B-mode, M-mode and Doppler-mode in 15 juvenile (3 weeks) and 15 adult (8 weeks) mice, during isoflurane anesthesia. M-mode measurements variability of left ventricle (LV) was determined.ResultsSeveral echocardiographic measurements significantly differ between juvenile and adult mice. Most of these measurements are related with cardiac dimensions. All B-mode measurements were different between juveniles and adults (higher in the adults), except for fractional area change (FAC). Ejection fraction (EF) and fractional shortening (FS), calculated from M-mode parameters, do not differ between juvenile and adult mice. Stroke volume (SV) and cardiac output (CO) were significantly different between juvenile and adult mice. SV was 31.93 ± 8.67 ?l in juveniles vs 70.61 ± 24.66 ?l in adults, ? < 0.001. CO was 12.06 ± 4.05 ml/min in juveniles vs 29.71 ± 10.13 ml/min in adults, ? < 0.001. No difference was found in mitral valve (MV) and tricuspid valve (TV) related parameters between juvenile and adult mice. It was demonstrated that variability of M-mode measurements of LV is minimal.ConclusionsThis study suggests that differences in cardiac dimensions, as wells as in pulmonary and aorta outflow parameters, were found between juvenile and adult mice. However, mitral and tricuspid inflow parameters seem to be similar between 3 weeks and 8 weeks mice. The reference values established in this study would contribute as a basis to future studies in post-natal cardiovascular development and diagnosing cardiovascular disorders in genetically modified mouse mutant lines.

Dataset Information

Studies of the H60a locus in C57BL/6 and 129/Sv mouse strains identify the H60a 3'UTR as a regulator of H60a expression.

Publications

Studies of the H60a locus in C57BL/6 and 129/Sv mouse strains identify the H60a 3'UTR as a regulator of H60a expression.

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