A SNF2 protein targets variable copy number repeats and thereby influences allele-specific expression

ATRX is an X-linked gene of the SWI/SNF family whose role in vivo is currently unknown. Mutations in ATRX cause syndromal mental retardation. ATRX binds to tandem repeat (TR) sequences both in heterochromatin (e.g. telomeres) and euchromatin. Genes associated with these TRs can be dysregulated when ATRX is mutated and the degree to which their expression changes is determined by the size of the TR, producing skewed allelic expression. This explains the nature of the affected genes, the variable phenotypes seen with identical ATRX mutations and also illustrates a new mechanism underlying variable penetrance. Many of the TRs in ATRX targets are G-rich and predicted to form non-B DNA structures (including G quadruplex) in vivo. We have shown that ATRX binds G quadruplex structures in vitro suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated. Overall design: 4 Human Erythroblast, 1 HEP3B and 1 Fibroblast ChIP-ChIP Sample For ChIP-Seq: one human erythroblasts, one mouse ES, one human erythroblast reference Sample, and one mouse ES input reference Sample.

ATRX是SWI/SNF家族（SWI/SNF family）的X连锁基因，其在体内（in vivo）的生理功能目前尚不明确。ATRX基因突变可引发综合征性智力障碍。ATRX可结合异染色质（如端粒）与常染色质中的串联重复序列（tandem repeat, TR）。当ATRX发生突变时，与这些TR序列相关的基因可出现表达失调，且其表达变化幅度由TR序列的长度决定，进而产生偏倚的等位基因表达。这一现象可解释受累基因的本质、携带相同ATRX突变个体所呈现的表型异质性，同时也阐明了一种全新的可变外显率潜在机制。ATRX靶向序列中的多数TR序列富含鸟嘌呤（G），且被预测可在体内（in vivo）形成非B型DNA结构（包括G四链体（G quadruplex））。我们的研究证实，ATRX可在体外（in vitro）结合G四链体结构，这提示了ATRX参与多种细胞核进程的潜在机制，以及ATRX突变时该机制如何受到扰动。实验整体设计：4份人成红细胞、1份HEP3B细胞及1份成纤维细胞的ChIP-ChIP样本；染色质免疫沉淀测序（ChIP-Seq）样本包括1份人成红细胞样本、1份小鼠胚胎干细胞（mouse ES）样本、1份人成红细胞对照样本及1份小鼠胚胎干细胞输入对照样本。