Abstract

BackgroundAging 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.ResultsOur 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.ConclusionsChanges 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.

Highlights

  • Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood

  • We sorted cells from pooled cohorts of male young and aged mice (12–15 mice per cohort) as shown in Fig. 1a and generated transcriptome, chromatin accessibility (ATAC-seq), histone modification (ChIP-seq), and chromosome conformation (Hi-C) datasets to identify changes associated with the aging phenotype

  • In addition to the genes related to insulin-like growth factor (IGF)-1 signaling, we identified other Differentially expressed gene (DEG) that have the potential to affect the aged phenotype in B cell precursors

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Summary

Introduction

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. Old age is accompanied by increased frailty including a breakdown in functionality of the adaptive immune system mediated by B and T lymphocytes [1]. This results in refractory responses to vaccination, loss of previously established immunity, and substantial increases in susceptibility to infection. Thereafter, the pre-BCR assumes control of both pre-B cell proliferation and IgK recombination [5, 6] This pro-B to pre-B transition requires IGF1 signaling [7]. Mast Grip Igf1r Large Nespas Irs Atrnl Zswim Igf2bp Exoc6b Fam189a1 Fmn Plxna Ptma Prkce Ccnd Sorcs Bard Xylt Camk1d Pde5a Rai Lgals Tmem108 Inpp4b Rftn Airn Mcf2l Cdkal Stac Nrxn Ddc Cask Aged States

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