Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation.

Area of Science:

• Genetics
• Molecular Biology
• Immunology

Background:

• Somatic hypermutation (SHM) is crucial for antibody diversification.
• SHM can introduce off-target mutations beyond immunoglobulin (Ig) genes.
• Understanding genomic regions prone to SHM is vital for genomic stability research.

Purpose of the Study:

• To identify genomic regions susceptible and resistant to somatic hypermutation.
• To elucidate the genomic and architectural features associated with SHM susceptibility.
• To develop a model for SHM targeting within the genome.

Main Methods:

• Utilized lentiviral SHM reporter vectors to map mutation patterns.
• Compared genomic and epigenetic features of mutation-prone ("hot") and mutation-resistant ("cold") topologically associated domains (TADs).
• Investigated the role of enhancers and B cell transcription factors in directing SHM.

Main Results:

• SHM susceptibility and resistance are often properties of entire TADs.
• Hot TADs are enriched for NIPBL, super-enhancers, paused RNA polymerase 2, and B cell transcription factors, despite equivalent transcription levels compared to cold TADs.
• Enhancers within hot TADs exhibit SHM targeting activity, and introducing Ig SHM elements can convert cold TADs into hot ones.

Conclusions:

• Genomic architecture, particularly TADs, plays a significant role in determining SHM susceptibility.
• SHM targeting is influenced by the interplay between cis-acting elements (like enhancers) and the dynamic, architectural properties of TADs.
• A model involving cooperative action of targeting elements and TAD properties explains SHM susceptibility.