Elevated Oxidative Stress Impairs Hematopoietic Progenitor Function in C57BL/6 Substrains

Morales-Hernández, Antonio; Martinat, Alice; Chabot, Ashley; Kang, Guolian; McKinney‐Freeman, Shannon

doi:10.1016/j.stemcr.2018.06.011

Cited by 15 publications

(16 citation statements)

References 47 publications

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“…Given the data presented herein and elsewhere ( Bourdi et al, 2011 ; Fontaine and Davis, 2016 ; Leskov et al, 2017 ; McCambridge et al, 2019 ; Mekada et al, 2009 ; Rao et al, 2020 ; Ripoll et al, 2012 ; Rydström, 2006 ; Toye et al, 2005 ; Vozenilek et al, 2018 ) and given that redox regulation affects many cellular processes ( Gambhir et al, 2019 ; Lingappan, 2018 ; Sun et al, 2020 ), Nnt emerges as a legitimate focus of concern. In addition, the presence of Nnt exons 8–12 provides a useful genetic marker to illustrate that a mouse strain is not on a pure 6J background, with genetic backgrounds, as shown herein and elsewhere, able to have a profound influence on phenotype ( Leskov et al, 2017 ; Morales-Hernandez et al, 2018 ; Salerno et al, 2019 ; Vozenilek et al, 2018 ; Williams et al, 2021 ; Wolf et al, 2016 ). We thus undertook a k-mer mining approach to interrogate the NCBI SRA ( Figure 8—figure supplement 1a ), which (at the time of analysis) contained 61,443 RNA-Seq Run Accessions listing ‘C57BL/6J’ in the strain field of the metadata.…”

Section: Resultsmentioning

confidence: 81%

“…NNT thereby sustains mitochondrial antioxidant capacity through generation of NADPH ( Ward et al, 2020 ), with the loss of active NNT in 6J mice associated with reduced ability to detoxify reactive oxygen species (ROS) via the glutathione and thioredoxin pathways ( McCambridge et al, 2019 ; Meimaridou et al, 2018 ; Ronchi et al, 2013 ; Rydström, 2006 ). As redox regulation is involved in many cellular processes ( Gambhir et al, 2019 ; Lingappan, 2018 ; Sun et al, 2020 ) and genetic backgrounds are known to affect phenotypes ( Leskov et al, 2017 ; Morales-Hernandez et al, 2018 ; Rao et al, 2020 ; Salerno et al, 2019 ; Vozenilek et al, 2018 ; Williams et al, 2021 ; Wolf et al, 2016 ), we sought to determine how many other studies in GMO mice might have been affected by 6J vs. 6N background differences using the Nnt gene as a genetic marker. k-mer mining of RNA-Seq datasets deposited in the NCBI Sequence Read Archive (SRA) revealed that ≈27% of Run Accessions and ≈38% of BioProjects listing the mouse strain as ‘C57BL/6J’ had Nnt reads inconsistent with a 6J background.…”

Section: Introductionmentioning

confidence: 99%

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Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Rawle

Dumenil

et al. 2022

eLife

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Granzyme A (GZMA) is a serine protease secreted by cytotoxic lymphocytes, with Gzma-/- mouse studies having informed our understanding of GZMA’s physiological function. We show herein that Gzma-/- mice have a mixed C57BL/6J and C57BL/6N genetic background and retain the full-length nicotinamide nucleotide transhydrogenase (Nnt) gene, whereas Nnt is truncated in C57BL/6J mice. Chikungunya viral arthritis was substantially ameliorated in Gzma-/- mice; however, the presence of Nnt and the C57BL/6N background, rather than loss of GZMA expression, was responsible for this phenotype. A new CRISPR active site mutant C57BL/6J GzmaS211A mouse provided the first insights into GZMA’s bioactivity free of background issues, with circulating proteolytically active GZMA promoting immune-stimulating and pro-inflammatory signatures. Remarkably, k-mer mining of the Sequence Read Archive illustrated that ≈27% of Run Accessions and ≈38% of BioProjects listing C57BL/6J as the mouse strain had Nnt sequencing reads inconsistent with a C57BL/6J genetic background. Nnt and C57BL/6N background issues have clearly complicated our understanding of GZMA and may similarly have influenced studies across a broad range of fields.

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Section: Resultsmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Rawle

Dumenil

et al. 2022

eLife

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show abstract

“…Finally, we wondered how general our results are. On the one hand, even in the C57BL/6 strain we used, mice from substrains J and N display genetic and phenotypic differences, some of which are immune related 60 . On the other hand, stronger IFN response in female macrophages is conserved all the way to birds 12 .…”

Section: Discussionmentioning

confidence: 99%

ImmGen report: sexual dimorphism in the immune system transcriptome

et al. 2019

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Sexual dimorphism in the mammalian immune system is manifested as more frequent and severe infectious diseases in males and, on the other hand, higher rates of autoimmune disease in females, yet insights underlying those differences are still lacking. Here we characterize sex differences in the immune system by RNA and ATAC sequence profiling of untreated and interferon-induced immune cell types in male and female mice. We detect very few differentially expressed genes between male and female immune cells except in macrophages from three different tissues. Accordingly, very few genomic regions display differences in accessibility between sexes. Transcriptional sexual dimorphism in macrophages is mediated by genes of innate immune pathways, and increases after interferon stimulation. Thus, the stronger immune response of females may be due to more activated innate immune pathways prior to pathogen invasion.

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“…Fig. 1 F, G) compared to C57BL/6J background [ 9 ], as only C57BL/6J mice exhibited increased oxidative stress [ 35 ]. In addition, C57BL/6J displayed insulin resistance and alterations in their metabolic response to diet-induced obesity compared to C57BL/6N mice, further highlighting the importance of the genetic background when assessing metabolism [ [36] , [37] , [38] ].…”

Section: Discussionmentioning

confidence: 99%

HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue

Hauffe

Rath

Schell

et al. 2021

Molecular Metabolism

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Objective Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance. Methods Control and heterozygous whole-body HSP60 knockout (Hsp60 +/− ) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis. Results Male Hsp60 +/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60 +/− mice in a glucose tolerance test. However, Hsp60 +/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance. Conclusions We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance.

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Elevated Oxidative Stress Impairs Hematopoietic Progenitor Function in C57BL/6 Substrains

Cited by 15 publications

References 47 publications

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

ImmGen report: sexual dimorphism in the immune system transcriptome

HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue

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