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

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.