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Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells

ABSTRACT: Background: Ageing is characterised by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of ageing on B cell development, we have profiled gene expression and chromatin features, including histone modifications and chromosome conformation focused on promoter interactions, globally in murine bone marrow pro-B and pre-B cells. Results: Our analysis revealed that the expression levels of most genes are generally preserved in B cell precursors isolated from aged as compared to young mice. Nonetheless, age-specific expression changes are observed at numerous genes and are underpinned by multi-layered alterations in chromatin structure, including chromatin accessibility, histone modifications, long-range promoter interactions and nuclear compartmentalisation. We identified transcriptional downregulation of components of the insulin-like growth factor signalling pathway, in particular downregulation of Irs1 and upregulation of miR/Let-7 expression, as a signature of the aged phenotype. Remarkably, these expression changes are associated with specific alterations in H3K27me3, suggesting that Polycomb-mediated repression plays a role in precursor B cell ageing. Conclusions: Components of the insulin-like growth factor signalling pathways are key targets of epigenetic regulation in ageing in bone marrow B cell precursors.

ORGANISM(S): Mus musculus

PROVIDER: GSE109671 | GEO | 2018/06/27

REPOSITORIES: GEO

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Project description:High fat diet (HFD) during early development may increase the susceptibility to metabolic diseases later in life. Adipose tissue is an important regulator of energy metabolism through secretion of endocrine and paracrine/autocrine factors. In the present study we first screened the expression profiles of about 500 miRNAs in visceral white adipose tissue (VAT) from mice fed a control diet (CD) and mice fed a matched HFD during three different life stages i) in utero (UT), ii) in utero and lactation (UL), iii) in utero until termination at age 23 weeks (WL). Fourteen differentially expressed miRNAs were identified and these miRNAs were used for prediction of targeted signalling pathways. In addition, analysis of high abundance miRNAs showed a marked downregulation of the miR-200 family members in the UT group. Subsequently, the transcript levels of 89 selected genes represented in the predicted signalling pathways were determined. Six genes (Deptor, Il6, Irs1, lep, Lpin1 and prkaa1) showed a significant differential expression due to HFD feeding compared to controls, and HFD treatment had significant effects on the WL-groups. The expression pattern of Deptor, Il6, Irs1, Lep genes showed a similar direction of change across all HFD treatment groups. The differential expression of Irs1 and Deptor genes points to a persistent modification of the insulin receptor – mTOR signalling network. This finding is supported by increased serum insulin and IGF-1 levels and impaired glucose regulation in the HFD groups. This study shows that developmental HFD can lead to persistent changes in VAT miRNA expression levels that is associated with a modification of key signalling pathways regulating energy metabolism also in animals with normal BMI.dy we have screened over 500 miRNAs for differential expression in visceral white adipose tissue (vWAT) between mice fed a control diet (CD; 10% kcal from fat) and mice fed a matched high fat diet (HFD; 45% kcal from fat) during three different life stages i) in utero (UT), ii) in utero and lactation (UL), iii) in utero until termination (WL). All animals were sacrifices at an age of 23 weeks.

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Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells

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