Three-dimensional chromatin reorganization regulates B cell development during ageing

Nat Cell Biol. 2024 Jun;26(6):991-1002. doi: 10.1038/s41556-024-01424-9. Epub 2024 Jun 12.

Abstract

The contribution of three-dimensional genome organization to physiological ageing is not well known. Here we show that large-scale chromatin reorganization distinguishes young and old bone marrow progenitor (pro-) B cells. These changes result in increased interactions at the compartment level and reduced interactions within topologically associated domains (TADs). The gene encoding Ebf1, a key B cell regulator, switches from compartment A to B with age. Genetically reducing Ebf1 recapitulates some features of old pro-B cells. TADs that are most reduced with age contain genes important for B cell development, including the immunoglobulin heavy chain (Igh) locus. Weaker intra-TAD interactions at Igh correlate with altered variable (V), diversity (D) and joining (J) gene recombination. Our observations implicate three-dimensional chromatin reorganization as a major driver of pro-B cell phenotypes that impair B lymphopoiesis with age.

MeSH terms

  • Aging* / genetics
  • Aging* / metabolism
  • Animals
  • B-Lymphocytes* / metabolism
  • Cell Differentiation
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly*
  • Immunoglobulin Heavy Chains* / genetics
  • Immunoglobulin Heavy Chains* / metabolism
  • Lymphopoiesis* / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Precursor Cells, B-Lymphoid / cytology
  • Precursor Cells, B-Lymphoid / immunology
  • Precursor Cells, B-Lymphoid / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Immunoglobulin Heavy Chains
  • Trans-Activators
  • Chromatin
  • Ebf1 protein, mouse