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Genome Biol. 2018 Sep 5;19(1):126. doi: 10.1186/s13059-018-1489-y.

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

Author information

1
Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK.
2
Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
3
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK.
4
Signalling, Babraham Institute, Cambridge, UK.
5
Present address: Université Clermont Auvergne, Inserm U1071, M2iSH, USC-INRA 2018, F-, 63000, Clermont-Ferrand, France.
6
Bioinformatics, Babraham Institute, Cambridge, UK.
7
Division of Cell Biology, Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
8
Functional Gene Control Group, MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN, UK.
9
Department of Biological Science, Florida State University, Tallahassee, FL, USA.
10
Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK. anne.corcoran@babraham.ac.uk.
11
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK. anne.corcoran@babraham.ac.uk.
12
Nuclear Dynamics Programme, Babraham Institute, Cambridge, UK. patrick.varga-weisz@essex.ac.uk.
13
School of Biological Sciences, University of Essex, Colchester, UK. patrick.varga-weisz@essex.ac.uk.

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.

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