Multiple polymorphic loci determine basal hepatic and splenic iron status in mice

Grant, Gemma R.; Robinson, Susan W.; Edwards, Richard E.; Clothier, Bruce; Davies, Rhian; Judah, David J.; Broman, Karl W.; Smith, Andrew G.

doi:10.1002/hep.21233

Cited by 18 publications

(30 citation statements)

References 50 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To this end, the list of putative hepcidin regulators generated in this study may serve as a resource, which could be integrated with data from genome-wide association, quantitative trait loci, and deep sequencing studies to identify new genetic modifiers of iron homeostasis. 9,[52][53][54] Future work based on the data from this RNAi screen is also expected to shed light on thus far unidentified links between HFE/TfR2 and BMP/HJV-dependent signaling. 24,25 Our current analysis has validated 4 proteins with adapter function and SH2 domains, which typically mediate protein-protein interactions involved in signal transduction.…”

Section: Discussionmentioning

confidence: 93%

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling

Mleczko-Sanecka

Roche

Silva

et al. 2014

Blood

View full text Add to dashboard Cite

Key Points• Genome-wide RNAi screen provides the first comprehensive list of putative hepatic hepcidin regulators.• Hepcidin suppression is linked to the control of mitogen stimulation and nutrient status via components of Ras/RAF MAPK and mTOR signaling.The hepatic hormone hepcidin is a key regulator of systemic iron metabolism. Its expression is largely regulated by 2 signaling pathways: the "iron-regulated" bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways. To obtain broader insights into cellular processes that modulate hepcidin transcription and to provide a resource to identify novel genetic modifiers of systemic iron homeostasis, we designed an RNA interference (RNAi) screen that monitors hepcidin promoter activity after the knockdown of 19 599 genes in hepatocarcinoma cells. Interestingly, many of the putative hepcidin activators play roles in signal transduction, inflammation, or transcription, and affect hepcidin transcription through BMP-responsive elements. Furthermore, our work sheds light on new components of the transcriptional machinery that maintain steady-state levels of hepcidin expression and its responses to the BMP-and interleukin-6-triggered signals. Notably, we discover hepcidin suppression mediated via components of Ras/ RAF MAPK and mTOR signaling, linking hepcidin transcriptional control to the pathways that respond to mitogen stimulation and nutrient status. Thus using a combination of RNAi screening, reverse phase protein arrays, and small molecules testing, we identify links between the control of systemic iron homeostasis and critical liver processes such as regeneration, response to injury, carcinogenesis, and nutrient metabolism. (Blood. 2014;123(10):1574-1585

show abstract

Section: Discussionmentioning

confidence: 93%

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling

Mleczko-Sanecka

Roche

Silva

et al. 2014

Blood

View full text Add to dashboard Cite

show abstract

“…The only validated gene in this QTL is Adam12, previously identified in a separate in silico mapping study as a single candidate for fat mass after 8 wk on an atherogenic diet (35). Third, a 0.64 Mb putative QTL on Chromosome 8 in males overlaps with a 19 cM QTL with effect on iron status in females (25). Fourth, a 0.32 Mb putative QTL on Chromosome 11 in females overlaps with a 39 cM QTL affecting basal liver iron status in females (25) and is close to the 3 cM QTL associated with hepatic iron loading reported by Bensaid et al (6).…”

Section: In Silico Mappingmentioning

confidence: 95%

“…First, a 0.29 Mb putative QTL (at ϳ34 Mb) on Chromosome 7 associated with iron levels in males in our study, overlaps with a 2.2 cM QTL affecting the severity of hepatic iron loading (6) and ventral midbrain iron content (29) in mice. Second, a 0.22 Mb putative QTL (at ϳ134 Mb) on Chromosome 7 in females, overlaps with a 31 cM QTL for basal liver iron in both males and males/females combined (25), and is also close to a reported QTL for ventral midbrain iron content (29). The only validated gene in this QTL is Adam12, previously identified in a separate in silico mapping study as a single candidate for fat mass after 8 wk on an atherogenic diet (35).…”

Section: In Silico Mappingmentioning

confidence: 98%

“…Several subsequent studies of iron metabolism indicated differences between inbred mice and/or supported a role of genetic control (13,20,25,28,61). A small number of these utilized a linkage analysis approach to map underlying genetic variation in intercross mice (25,28). In this study, we describe use of a new approach, in silico mapping, to identify genetic regions underlying the variation in iron metabolism between inbred mouse strains.…”

mentioning

confidence: 96%

“…C57BL/6J and BALB/cJ mouse strains required 10 times more dietary iron to saturate their serum transferrin than DBA/2J and AKR/J mice (47). Several subsequent studies of iron metabolism indicated differences between inbred mice and/or supported a role of genetic control (13,20,25,28,61). A small number of these utilized a linkage analysis approach to map underlying genetic variation in intercross mice (25,28).…”

mentioning

confidence: 97%

See 2 more Smart Citations

In silico QTL mapping of basal liver iron levels in inbred mouse strains

McLachlan

Lee

Steele

et al. 2011

Physiological Genomics

View full text Add to dashboard Cite

Both iron deficiency and iron excess are detrimental in many organisms, and previous studies in both mice and humans suggest that genetic variation may influence iron status in mammals. However, these genetic factors are not well defined. To address this issue, we measured basal liver iron levels in 18 inbred strains of mice of both sexes on a defined iron diet and found ∼4-fold variation in liver iron in males (lowest 153 μg/g, highest 661 μg/g) and ∼3-fold variation in females (lowest 222 μg/g, highest 658 μg/g). We carried out a genome-wide association mapping to identify haplotypes underlying differences in liver iron and three other related traits (copper and zinc liver levels, and plasma diferric transferrin levels) in a subset of 14 inbred strains for which genotype information was available. We identified two putative quantitative trait loci (QTL) that contain genes with a known role in iron metabolism: Eif2ak1 and Igf2r. We also identified four putative QTL that reside in previously identified iron-related QTL and 22 novel putative QTL. The most promising putative QTL include a 0.22 Mb region on Chromosome 7 and a 0.32 Mb region on Chromosome 11 that both contain only one candidate gene, Adam12 and Gria1, respectively. Identified putative QTL are good candidates for further refinement and subsequent functional studies.

show abstract

Genetic analysis of iron-deficiency effects on the mouse spleen

et al. 2011

View full text Add to dashboard Cite

Iron homeostasis is crucial to many biological functions in nearly all organisms, with roles ranging from oxygen transport to immune function. Disruption of iron homeostasis may result in iron overload or iron deficiency. Iron deficiency may have severe consequences, including anemia or changes in immune or neurotransmitter systems. Here, we report the variability phenotypic iron tissue loss and splenomegaly as well as the associated quantitative trait loci (QTL), polymorphic areas in the mouse genome which may contain one or more genes that play a role in spleen iron concentration or spleen weight under each dietary treatment. Mice from twenty-six BXD/Ty recombinant inbred strains, including the parent C57BL/6 and DBA/2 strains, were randomly assigned to adequate iron or iron deficient diets at weaning. After 120 days, splenomegaly was measured by spleen weight, and spleen iron was assessed using a modified spectrophotometry technique. QTL analyses and gene expression comparisons were then conducted using the WebQTL GenetNetwork. We observed wide, genetic-based variability in splenomegaly and spleen iron loss in BXD/Ty recombinant inbred strains fed an iron deficient diet. Moreover, we identified several suggestive QTL. Matching our QTL with gene expression data from the spleen revealed candidate genes. Our work shows that individual differences in splenomegaly response to iron deficiency are influenced at least partly by genetic constitution. We propose mechanistic hypotheses by which splenomegaly may result from iron deficiency.

show abstract

Multiple polymorphic loci determine basal hepatic and splenic iron status in mice

Cited by 18 publications

References 50 publications

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling

In silico QTL mapping of basal liver iron levels in inbred mouse strains

Genetic analysis of iron-deficiency effects on the mouse spleen

Contact Info

Product

Resources

About