Three-dimensional chromatin reorganization regulates B cell development during ageing.

Area of Science:

• Genomics
• Immunology
• Aging Research

Background:

• The role of three-dimensional genome organization in physiological aging is largely unknown.
• Cellular aging affects various biological processes, including immune cell development and function.

Purpose of the Study:

• To investigate how three-dimensional genome organization changes during physiological aging in bone marrow progenitor (pro-) B cells.
• To determine the impact of these organizational changes on B cell development and function.

Main Methods:

• Comparative analysis of chromatin organization in young versus old pro-B cells using advanced genomic techniques.
• Gene expression analysis and functional assays to assess the impact of chromatin changes.

Main Results:

• Significant large-scale chromatin reorganization distinguishes young and old pro-B cells, characterized by increased compartment-level interactions and decreased interactions within topologically associated domains (TADs).
• The key B cell regulator Ebf1 gene shifts from compartment A to B with age, and its genetic reduction mimics some aging-related pro-B cell features.
• Aging-associated reduction in TADs impacts genes crucial for B cell development, including the immunoglobulin heavy chain (Igh) locus, correlating with altered V(D)J recombination.

Conclusions:

• Three-dimensional chromatin reorganization is a significant driver of pro-B cell phenotypes observed during aging.
• These age-related chromatin alterations contribute to impaired B lymphopoiesis.