Chromatin Modifications in 22q11.2 Deletion Syndrome

Area of Science:

• Immunology
• Epigenetics
• Genetics

Background:

• Chromosome 22q11.2 deletion syndrome is a common primary immunodeficiency.
• Early effects include thymic hypoplasia and low T cell numbers.
• Later manifestations like atopy, autoimmunity, and hypogammaglobulinemia have unclear causes.

Purpose of the Study:

• To investigate alterations in histone modifications using an unbiased approach.
• To identify durable chromatin changes influencing cell behavior in 22q11.2 deletion syndrome.

Main Methods:

• ChIP-seq analysis of CD4 T cells and CD19 B cells for histone marks (H3K4me3, H3K27ac, H4ac).
• RNA-seq analysis of CD4 T cells to define transcriptomic effects.
• Luminex assay to examine serum cytokines.

Main Results:

• Globally increased histone marks of transcriptional activation in CD4 T cells, linked to T cell activation and inflammation.
• Minimally altered epigenetic landscape in B cells.
• Markedly altered chromatin observed adjacent to the deletion in both cell types ('edge' effect).

Conclusions:

• Individuals with 22q11.2 deletion exhibit altered CD4 T cell chromatin and transcriptome, aligning with epigenomic changes.
• These findings support a disease model involving qualitative T cell changes alongside known quantitative defects.
• The study provides novel insights into the qualitative T cell differences in 22q11.2 deletion syndrome.