Age-associated chromatin re-organization in progenitor B cells

Three-dimensional (3D) organization of the genome is essential for precise patterns of gene expression required for biological processes, however its role in physiological aging is not known.Here we show that large scale chromatin re-organization distinguishes bone marrow progenitor (pro-) B cells of old mice from that of young mice.These changes result in increased interactions at the compartment level and reduced interactions within topologically associated domains (TADs).One genomic region that transitions from compartment A to B with age contains the gene encoding Ebf1, a key regulator of normal B cell development.Genetically reducing Ebf1 recapitulates some features of old pro-B cells.TADs that are most reduced with age also harbor genes important for function and development of pro-B cells, including the immunoglobulin heavy chain (IgH) gene locus.Weaker intra-TAD interactions at IgH correlate with reduced utilization of distally located variable gene segments in VDJ recombination.Our observations implicate 3D chromatin re-organization as a major driver of pro-B cell phenotypes that impair B lymphopoiesis with age.