Title |
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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Published in |
Genome Biology, September 2018
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DOI | 10.1186/s13059-018-1489-y |
Pubmed ID | |
Authors |
Hashem Koohy, Daniel J. Bolland, Louise S. Matheson, Stefan Schoenfelder, Claudia Stellato, Andrew Dimond, Csilla Várnai, Peter Chovanec, Tamara Chessa, Jeremy Denizot, Raquel Manzano Garcia, Steven W. Wingett, Paula Freire-Pritchett, Takashi Nagano, Phillip Hawkins, Len Stephens, Sarah Elderkin, Mikhail Spivakov, Peter Fraser, Anne E. Corcoran, Patrick D. Varga-Weisz |
Abstract |
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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