Accessibility changes across the mouse Igh-V locus during B cell development

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• B and T lymphocytes undergo chromatin remodeling at antigen receptor loci during development.
• This remodeling regulates V(D)J recombinase access to specific gene segments.
• Understanding locus accessibility is crucial for lymphocyte development and gene rearrangement.

Purpose of the Study:

• To investigate tissue and stage-specific chromatin structure changes at VHJ558, VH10, and VHS107 gene families.
• To examine the relationship between germ-line transcription, nuclease sensitivity, and chromatin accessibility.
• To determine the temporal dynamics of Igh-V locus accessibility during B cell development.

Main Methods:

• Utilized germ-line transcription as a marker for gene accessibility.
• Assessed chromatin structure by measuring DNase I sensitivity.
• Examined specific V(D)J gene families (VHJ558, VH10, VHS107) across different B cell stages.

Main Results:

• Germ-line VH transcripts were detected in pro- and pre-B cells for all families.
• Transcripts for VH10 and VHS107 persisted into immature and mature B cell stages, unlike VHJ558.
• Unexpectedly low nuclease sensitivity was observed across most VH loci, with modest sensitivity at VHJ558 in early B cells.
• The entire Igh-V locus appears accessible in early B cells, with accessibility changes occurring non-uniformly across the array.

Conclusions:

• The Igh-V locus undergoes dynamic chromatin accessibility changes during B cell development.
• Accessibility is not uniform across the VH array, suggesting complex regulatory mechanisms.
• Multiple long-range elements likely coordinate VH gene targeting for V(D)J recombination.