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Koohy, Hashem; Bolland, Daniel J; Matheson, Louise S; Schoenfelder, Stefan; Stellato, Claudia; Dimond, Andrew; Várnai, Csilla; Chovanec, Peter; Chessa, Tamara; Denizot, Jeremy; Manzano Garcia, Raquel; Wingett, Steven W; Freire-Pritchett, Paula; Nagano, Takashi; Hawkins, Phillip; Stephens, Len; Elderkin, Sarah; Spivakov, Mikhail; Fraser, Peter; Corcoran, Anne E; Varga-Weisz, Patrick D
Genome Biology, 09/2018, Volume: 19, Issue: 1Journal Article
Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice. Our analysis reveals that the expression levels of most genes are generally preserved in B cell precursors isolated from aged compared with young mice. Nonetheless, age-specific expression changes are observed at numerous genes, including microRNA encoding genes. Importantly, these changes are underpinned by multi-layered alterations in chromatin structure, including chromatin accessibility, histone modifications, long-range promoter interactions, and nuclear compartmentalization. Previous work has shown that differentiation is linked to changes in promoter-regulatory element interactions. We find that aging in B cell precursors is accompanied by rewiring of such interactions. We identify transcriptional downregulation of components of the insulin-like growth factor signaling pathway, in particular downregulation of Irs1 and upregulation of Let-7 microRNA expression, as a signature of the aged phenotype. These changes in expression are associated with specific alterations in H3K27me3 occupancy, suggesting that Polycomb-mediated repression plays a role in precursor B cell aging. Changes in chromatin and 3D genome organization play an important role in shaping the altered gene expression profile of aged precursor B cells. Components of the insulin-like growth factor signaling pathways are key targets of epigenetic regulation in aging in bone marrow B cell precursors.
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