ABSTRACT

CTCF is a master regulator of gene transcription and chromatin organisation with occupancy at thousands of DNA target sites genome-wide. While CTCF is essential for cell survival, CTCF haploinsufficiency is associated with tumour development and hypermethylation. Increasing evidence demonstrates CTCF as a key player in several mechanisms regulating alternative splicing (AS), however, the genome-wide impact of Ctcf dosage on AS has not been investigated.

We examined the effect of Ctcf haploinsufficiency on gene expression and AS in five tissues from Ctcf hemizygous (Ctcf ^+/-) mice. Reduced Ctcf levels caused distinct tissue-specific differences in gene expression and AS in all tissues. An increase in intron retention (IR) was observed in Ctcf ^+/- liver and kidney. In liver, this specifically impacted genes associated with cytoskeletal organisation, splicing and metabolism. Strikingly, most differentially retained introns were short, with a high GC content and enriched in Ctcf binding sites in their proximal upstream genomic region. This study provides new insights into the effects of CTCF haploinsufficiency on organ transcriptomes and the role of CTCF in AS regulation.

摘要

CTCF 是基因转录和染色质组织的主要调节因子，占据全基因组数千个 DNA 靶位点。虽然 CTCF 对细胞存活至关重要，但 CTCF 单倍体不足与肿瘤发展和高甲基化有关。越来越多的证据表明 CTCF 是调节选择性剪接 (AS) 的几种机制的关键参与者，但是，尚未研究Ctcf剂量对 AS的全基因组影响。

我们检查了Ctcf 单倍剂量不足对Ctcf半合子 ( Ctcf ^+/- ) 小鼠的五种组织中基因表达和 AS 的影响。Ctcf水平降低导致所有组织中基因表达和 AS 的明显组织特异性差异。在Ctcf ^+/-肝脏和肾脏中观察到内含子保留 (IR) 增加。在肝脏中，这特别影响与细胞骨架组织、剪接和代谢相关的基因。引人注目的是，大多数差异保留的内含子都很短，GC 含量高，并且在其近端上游基因组区域富含 Ctcf 结合位点。这项研究为CTCF的影响提供了新的见解 器官转录组的单倍不足和 CTCF 在 AS 调节中的作用。