The switch/sucrose non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeller that regulates the spacing of nucleosomes and thereby controls gene expression. Heterozygous mutations in genes encoding subunits of the SWI/SNF complex have been reported in individuals with Coffin-Siris syndrome (CSS), with the majority of the mutations in ARID1B. CSS is a rare congenital disorder characterized by facial dysmorphisms, digital anomalies, and variable intellectual disability. We hypothesized that mutations in genes encoding subunits of the ubiquitously expressed SWI/SNF complex may lead to alterations of the nucleosome profiles in different cell types. We performed the first study on CSS-patient samples and investigated the nucleosome landscapes of cell-free DNA (cfDNA) isolated from blood plasma by whole-genome sequencing. In addition, we studied the nucleosome landscapes of CD14+ monocytes from CSS-affected individuals by nucleosome occupancy and methylome-sequencing (NOMe-seq) as well as their expression profiles. In cfDNA of CSS-affected individuals with heterozygous ARID1B mutations, we did not observe major changes in the nucleosome profile around transcription start sites. In CD14+ monocytes, we found few genomic regions with different nucleosome occupancy when compared to controls. RNA-seq analysis of CD14+ monocytes of these individuals detected only few differentially expressed genes, which were not in proximity to any of the identified differential nucleosome-depleted regions. In conclusion, we show that heterozygous mutations in the human SWI/SNF subunit ARID1B do not have a major impact on the nucleosome landscape or gene expression in blood cells. This might be due to functional redundancy, cell-type specificity, or alternative functions of ARID1B.

中文翻译：

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Coffin-Siris 综合征个体核小体景观的全基因组分析

开关/蔗糖非发酵 (SWI/SNF) 复合物是一种 ATP 依赖性染色质重塑剂，可调节核小体的间距，从而控制基因表达。据报道，在 Coffin-Siris 综合征 (CSS) 患者中，编码 SWI/SNF 复合体亚基的基因发生杂合突变，其中大部分突变发生在 ARID1B 中。CSS 是一种罕见的先天性疾病，其特征是面部畸形、数字异常和可变的智力障碍。我们假设编码无处不在表达的 SWI/SNF 复合体亚基的基因突变可能导致不同细胞类型中核小体谱的改变。我们对 CSS 患者样本进行了第一项研究，并通过全基因组测序研究了从血浆中分离出的无细胞 DNA (cfDNA) 的核小体景观。此外，我们通过核小体占据和甲基化测序 (NOMe-seq) 以及它们的表达谱研究了来自 CSS 影响个体的 CD14+ 单核细胞的核小体景观。在具有杂合 ARID1B 突变的受 CSS 影响的个体的 cfDNA 中，我们没有观察到转录起始位点周围核小体谱的重大变化。在 CD14+ 单核细胞中，与对照相比，我们发现很少有具有不同核小体占有率的基因组区域。这些个体的 CD14+ 单核细胞的 RNA-seq 分析仅检测到很少的差异表达基因，这些基因不靠近任何已识别的差异核小体耗尽区域。总之，我们表明人类 SWI/SNF 亚基 ARID1B 中的杂合突变对血细胞中的核小体景观或基因表达没有重大影响。