Purpose

Chromosome 22q11.2 deletion syndrome is a common inborn error of immunity. The early consequences of thymic hypoplasia are low T cell numbers. Later in life, atopy, autoimmunity, inflammation, and evolving hypogammaglobulinemia can occur and the causes of these features are not understood. This study utilized an unbiased discovery approach to define alterations in histone modifications. Our goal was to identify durable chromatin changes that could influence cell behavior.

Methods

CD4 T cells and CD19 B cells underwent ChIP-seq analysis using antibodies to H3K4me3, H3K27ac, and H4ac. RNA effects were defined in CD4 T cells by RNA-seq. Serum cytokines were examined by Luminex.

Results

Histone marks of transcriptional activation at CD4 T cell promoters and enhancers were globally increased. The promoter activation signature had elements related to T cell activation and inflammation, concordant with effects seen in the transcriptome. B cells, in contrast, had a minimally altered epigenetic landscape in 22q11.2. Both cell types had an “edge” effect with markedly altered chromatin adjacent to the deletion.

Conclusions

People with 22q11.2 deletion have altered CD4 T cell chromatin and a transcriptome concordant with the changes in the epigenome. These effects support a disease model where qualitative changes to T cells occur in addition to quantitative defects that have been well characterized. This study offers unique insight into qualitative differences in the T cells in 22q11.2 deletion, an aspect that has received limited attention.

中文翻译：

---

22q11.2 缺失综合征中的染色质修饰

目的

染色体 22q11.2 缺失综合征是一种常见的先天性免疫缺陷。胸腺发育不全的早期后果是 T 细胞数量减少。在以后的生活中，可能会出现特应性、自身免疫、炎症和不断发展的低丙种球蛋白血症，并且这些特征的原因尚不清楚。本研究利用一种公正的发现方法来定义组蛋白修饰的变化。我们的目标是确定可能影响细胞行为的持久染色质变化。

方法

CD4 T 细胞和 CD19 B 细胞使用针对 H3K4me3、H3K27ac 和 H4ac 的抗体进行了 ChIP-seq 分析。通过 RNA-seq 在 CD4 T 细胞中定义 RNA 效应。Luminex检测血清细胞因子。

结果

CD4 T 细胞启动子和增强子处转录激活的组蛋白标记在全球范围内增加。启动子激活特征具有与 T 细胞激活和炎症相关的元素，与转录组中观察到的效果一致。相比之下，B 细胞在 22q11.2 的表观遗传景观发生了微小的变化。两种细胞类型都具有“边缘”效应，与缺失相邻的染色质显着改变。

结论

22q11.2 缺失的人改变了 CD4 T 细胞染色质和与表观基因组变化一致的转录组。这些效应支持了一个疾病模型，其中除了已充分表征的定量缺陷外，T 细胞还会发生质的变化。这项研究提供了对 22q11.2 缺失中 T 细胞质量差异的独特见解，这一方面受到的关注有限。