Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells
Year: 2018
Type: article
Abstract: BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
Source: Genome biology
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
Institutions: Babraham Institute, University of Oxford, MRC Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, Inserm, Université Clermont Auvergne, Microbe, Intestine, Inflammation and Host Susceptibility, MRC Laboratory of Molecular Biology, Medical Research Council, MRC London Institute of Medical Sciences, Florida State University, University of Essex
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,490
Awards: How changes in nutrient availability are sensed and shape metabolism and growth, G1990583613, Computational systems biology of ageing in haematopoiesis and the immune system, Signalling mechanisms that determine the rate of ageing, Genomic and epigenomic analysis of ageing in haematopoiesis and the immune system., G3074483764, To define the molecular mechanisms that determine cellular and organismal longevity, G4413445385, To map the organisation of nutrient signalling pathways, G5058624343, Develop a mechanistic understanding of how transcriptional and posttranscriptional regulation of gene expression is coordinated by signal transduction pathways., G6160911136, G6580186668, a novel strategy toward chromatin dynamics based on precise single-cell information, G7255661211, Immune homeostasis and the immune response, G8755156122
OpenAlex ID: W2889376190