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Genome Organization And Chromatin Analysis Identify Transcriptional Downregulation Of Insulin-like Growth Factor Signaling As A Hallmark Of Aging In Developing B Cells

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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Name(s): Koohy, Hashem, author
Bolland, Daniel J., author
Matheson, Louise S., author
Schoenfelder, Stefan, author
Stellato, Claudia, author
Dimond, Andrew, author
Varnai, Csilla, author
Chovanec, Peter, author
Chessa, Tamara, author
Denizot, Jeremy, author
Garcia, Raquel Manzano, author
Wingett, Steven W., author
Freire-Pritchett, Paula, author
Nagano, Takashi, author
Hawkins, Phillip, author
Stephens, Len, author
Elderkin, Sarah, author
Spivakov, Mikhail, author
Fraser, Peter, author
Corcoran, Anne E., author
Varga-Weisz, Patrick D., author
Type of Resource: text
Genre: Journal Article
Text
Journal Article
Date Issued: 2018-09-05
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_libsubv1_wos_000443725200001 (IID), 10.1186/s13059-018-1489-y (DOI)
Keywords: skeletal-muscle, elements, bone-marrow, receptor, capture hi-c, aged mice reflects, chromosome organization, integrative analysis, large gene lists, lymphopoiesis
Publication Note: The publisher’s version of record is available at https://doi.org/10.1186/s13059-018-1489-y
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000443725200001
Owner Institution: FSU
Is Part Of: Genome Biology.
1474-760X
Issue: vol. 19

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Koohy, H., Bolland, D. J., Matheson, L. S., Schoenfelder, S., Stellato, C., Dimond, A., … Varga-Weisz, P. D. (2018). Genome Organization And Chromatin Analysis Identify Transcriptional Downregulation Of Insulin-like Growth Factor Signaling As A Hallmark Of Aging In Developing B Cells. Genome Biology. Retrieved from http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000443725200001