<i>Ctcf</i> haploinsufficiency mediates intron retention in a tissue-specific manner

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 <i>Ctcf</i> dosage on AS has not been investigated. We examined the effect of <i>Ctcf</i> haploinsufficiency on gene expression and AS in five tissues from <i>Ctcf</i> hemizygous (<i>Ctcf</i> ^+/-) mice. Reduced <i>Ctcf</i> levels caused distinct tissue-specific differences in gene expression and AS in all tissues. An increase in intron retention (IR) was observed in <i>Ctcf</i> ^+/- 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 <i>CTCF</i> haploinsufficiency on organ transcriptomes and the role of CTCF in AS regulation.

CTCF（CCCTC结合因子，CCCTC-binding factor）是基因转录与染色质组织的主调控因子，可在全基因组范围内结合数千个DNA靶位点。尽管CTCF对细胞存活至关重要，但CTCF单倍体剂量不足与肿瘤发生及高甲基化密切相关。越来越多的证据表明，CTCF在调控可变剪接（alternative splicing，AS）的多种机制中发挥关键作用，但目前尚未有研究探讨Ctcf剂量对AS的全基因组影响。本研究以半合子Ctcf（Ctcf +/-）小鼠的五种组织为研究材料，分析了Ctcf单倍体剂量不足对基因表达与可变剪接的影响。Ctcf表达水平降低会在所有组织中引发显著的组织特异性基因表达与可变剪接差异。研究发现，Ctcf +/-小鼠的肝脏与肾脏中，内含子滞留（intron retention，IR）现象显著增多。在肝脏组织中，此类变化特异性地影响了与细胞骨架组织、剪接调控及代谢相关的基因。值得注意的是，绝大多数差异滞留内含子长度较短，且具有较高的GC含量，其近端上游基因组区域富集有CTCF结合位点。本研究为解析CTCF单倍体剂量不足对器官转录组的影响，以及CTCF在可变剪接调控中的作用提供了全新的见解。

搜集汇总

背景与挑战

背景概述

该数据集基于对Ctcf半合子小鼠五种组织的研究，探讨了Ctcf单倍体不足对基因表达和替代剪接的影响，特别关注内含子保留的组织特异性现象。研究发现，在肝脏和肾脏中，Ctcf水平降低导致内含子保留增加，主要影响与细胞骨架组织、剪接和代谢相关的基因，且这些内含子通常较短、GC含量高并富含Ctcf结合位点。数据集提供了补充表格支持分析，揭示了CTCF在基因调控中的新机制。