Genome-wide and single-cell analyses reveal a context dependent relationship between CBP recruitment and gene expression.
Genome-wide and single-cell analyses reveal a context dependent relationship between CBP recruitment and gene expression.
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DOI：
10.1093/nar/gku827
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发表时间：
2014-10
影响因子：
14.9
通讯作者：
Brindle PK
中科院分区：
文献类型：
--
作者：
Kasper LH;Qu C;Obenauer JC;McGoldrick DJ;Brindle PK
组蛋白H3K18和H3K27乙酰转移酶CBP （CREBBP）和p300 （EP300）的全基因组分布用于定位增强子和启动子，但这些元件是否在功能上需要CBP/p300仍不确定。在这里，我们比较了野生型和CBP/p300双敲除（dKO）成纤维细胞中CBP的全球募集与基因表达。使用CBP缺失细胞作为对照的ChIP-seq显示，20%的组成性表达基因在附近的CBP募集，但令人惊讶的是，这些基因中有四分之三在dKO细胞中不受影响或轻微激活。计算定义的增强子-启动子单元（epu）在增强子样元件附近有一个CBP峰，更具有预测性，CBP/p300缺失会减弱40%的这类组成性表达基因的表达。检测信号响应（缺氧诱导因子）基因显示，97%的基因在可诱导CBP峰值的50千碱基范围内，其中70%需要CBP/p300才能完全诱导。出乎意料的是，大多数可诱导的CBP峰发生在信号无应答基因附近。最后，单细胞表达分析揭示了额外的环境依赖性，其中一些信号应答基因在单个细胞中并不一致地依赖于CBP/p300。虽然CBP/p300需要在单细胞中完全诱导一些基因，但对于其他基因，CBP/p300增加了最大表达的可能性。因此，靶基因环境可能通过多种机制影响CBP/p300的转录需求。
Genome-wide distribution of histone H3K18 and H3K27 acetyltransferases, CBP (CREBBP) and p300 (EP300), is used to map enhancers and promoters, but whether these elements functionally require CBP/p300 remains largely uncertain. Here we compared global CBP recruitment with gene expression in wild-type and CBP/p300 double-knockout (dKO) fibroblasts. ChIP-seq using CBP-null cells as a control revealed nearby CBP recruitment for 20% of constitutively-expressed genes, but surprisingly, three-quarters of these genes were unaffected or slightly activated in dKO cells. Computationally defined enhancer-promoter-units (EPUs) having a CBP peak near the enhancer-like element were more predictive, with CBP/p300 deletion attenuating expression of 40% of such constitutively-expressed genes. Examining signal-responsive (Hypoxia Inducible Factor) genes showed that 97% were within 50 kilobases of an inducible CBP peak, and 70% of these required CBP/p300 for full induction. Unexpectedly, most inducible CBP peaks occurred near signal-nonresponsive genes. Finally, single-cell expression analysis revealed additional context dependence where some signal-responsive genes were not uniformly dependent on CBP/p300 in individual cells. While CBP/p300 was needed for full induction of some genes in single-cells, for other genes CBP/p300 increased the probability of maximal expression. Thus, target gene context influences the transcriptional requirement for CBP/p300, possibly by multiple mechanisms.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
作者：
Arany, Z;Huang, LE;Livingston, DM
通讯作者：
Livingston, DM
影响因子：
64.8
作者：
DuPage, Michel;Mazumdar, Claire;Schmidt, Leah M.;Cheung, Ann F.;Jacks, Tyler
通讯作者：
Jacks, Tyler
影响因子：
64.5
作者：
Altschuler SJ;Wu LF
通讯作者：
Wu LF