The contribution of cohesin-SA1 to chromatin architecture and gene expression in two murine tissues [RNA-seq]

Cohesin, which consists of SMC1, SMC3, Rad21 and either SA1 or SA2, topologically embraces the chromatin fibers to hold sister chromatids together and to stabilize chromatin loops. Increasing evidence indicates that these loops are the organizing principle of higher-order chromatin architecture, which in turn is critical for gene expression. To determine how cohesin contributes to the establishment of tissue-specific transcriptional programs, we compared genome-wide cohesin distribution, gene expression and chromatin architecture in cerebral cortex and pancreas from adult mice. More than one third of cohesin binding sites differ between the two tissues and these are enriched at the regulatory regions of tissue-specific genes. Cohesin colocalizes extensively with the CCCTC-binding factor (CTCF). Cohesin/CTCF sites at active enhancers and promoters contain, at least, cohesin-SA1 whereas either cohesin-SA1 or cohesin-SA2 are present at active promoters independently of CTCF. Analyses of chromatin contacts at the Protocadherin gene cluster and the Regenerating islet-derived (Reg) gene cluster, mostly expressed in brain and pancreas respectively, revealed remarkable differences in the architecture of these loci in the two tissues that correlate with the presence of cohesin. Moreover, we found decreased binding of cohesin and reduced transcription of the Reg genes in the pancreas of SA1 heterozygous mice. Given that Reg proteins are involved in the control of inflammation in pancreas, such reduction may contribute to the increased incidence of pancreatic cancer reported in these animals. Examination of the relationship between gene expression, genome wide cohesin distribution and chromatin structure黏连蛋白（Cohesin）由SMC1、SMC3、Rad21以及SA1或SA2组成，以拓扑方式环绕染色质纤维，从而将姐妹染色单体维系在一起并稳定染色质环。越来越多的证据表明，这些染色质环是高级染色质结构的组织核心，而高级染色质结构对基因表达至关重要。为探究黏连蛋白如何参与组织特异性转录程序的建立，我们对成年小鼠大脑皮层与胰腺中的全基因组黏连蛋白分布、基因表达及染色质结构进行了比较分析。两个组织间超过三分之一的黏连蛋白结合位点存在差异，且这些差异位点在组织特异性基因的调控区域中显著富集。黏连蛋白与CCCTC结合因子（CTCF）存在广泛的共定位现象。位于活性增强子与启动子处的黏连蛋白/CTCF位点至少包含黏连蛋白-SA1，而独立于CTCF的活性启动子处则可存在黏连蛋白-SA1或黏连蛋白-SA2。对分别主要在脑与胰腺中表达的原钙粘蛋白基因簇以及胰岛再生相关（Reg）基因簇的染色质互作进行分析后发现，这两个基因座在两种组织中的结构存在显著差异，且该差异与黏连蛋白的存在密切相关。此外，我们在SA1杂合小鼠的胰腺中发现黏连蛋白结合能力下降，且Reg基因的转录水平降低。鉴于Reg蛋白参与胰腺炎症的调控，这种转录水平的降低可能会加剧此前报道中这类杂合小鼠胰腺癌发病率的升高。本研究还对基因表达、全基因组黏连蛋白分布与染色质结构之间的关联进行了考察。