Genomic Medicine Laboratory, Quebec Heart and Lung Institute, Laval University, Quebec, Canada.
Quebec Heart and Lung Institute, Laval University, Quebec, Canada.
Sci Rep. 2023 Apr 5;13(1):5594. doi: 10.1038/s41598-023-32669-3.
Evidence indicates that enhancers are transcriptionally active. Herein, we investigated transcriptionally active enhancers by using cap analysis of gene expression (CAGE) combined with epigenetic marks and chromatin interactions. We identified CAGE-tag highly active (CHA) enhancers as distant regulatory elements with CAGE-tag ≥ 90th percentile and overlapping with H3K27ac peaks (4.5% of enhancers). CHA enhancers were conserved between mouse and man and were independent from super-enhancers in predicting cell identity with lower P-values. CHA enhancers had increased open chromatin and a higher recruitment of cell-specific transcription factors as well as molecules involved in 3D genome interactions. HiChIP analysis of enhancer-promoter looping indicated that CHA enhancers had a higher density of anchor loops when compared to regular enhancers. A subset of CHA enhancers and promoters characterized by a high density of chromatin loops and forming hub regulatory units were connected to the promoter of immediate early response genes, genes involved in cancer and encoding for transcription factors. Promoter of genes within hub CHA regulatory units were less likely to be paused. CHA enhancers were enriched in gene variants associated with autoimmune disorders and had looping with causal candidate genes as revealed by Mendelian randomization. Hence, CHA enhancers form a dense hierarchical network of chromatin interactions between regulatory elements and genes involved in cell identity and disorders.
有证据表明，增强子具有转录活性。在此，我们通过结合表观遗传标记和染色质相互作用，利用基因表达的帽分析（CAGE）来研究转录活性增强子。我们将 CAGE 标签高活性（CHA）增强子鉴定为具有 CAGE 标签≥90 百分位数并与 H3K27ac 峰重叠的远距离调节元件（占增强子的 4.5%）。CHA 增强子在小鼠和人类之间是保守的，并且在预测细胞身份方面独立于超级增强子，其 P 值较低。CHA 增强子具有开放染色质增加的特点，并且募集了更多的细胞特异性转录因子以及参与 3D 基因组相互作用的分子。增强子-启动子环looping 的 HiChIP 分析表明，与常规增强子相比，CHA 增强子具有更高密度的锚环looping。CHA 增强子和启动子的子集具有高密的染色质环looping，并形成枢纽调节单元，与即时早期反应基因、癌症相关基因和转录因子的启动子相连。位于枢纽 CHA 调节单元内的基因启动子不太可能暂停。CHA 增强子富含与自身免疫性疾病相关的基因变异体，并且通过孟德尔随机化显示与候选因果基因具有环looping。因此，CHA 增强子形成了一个涉及细胞身份和疾病的调节元件与基因之间的密集层次化染色质相互作用网络。
