Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming.,Nature Chemical Biology

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Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2019-04-08 , DOI: 10.1038/s41589-019-0264-z
Ayyub Ebrahimi _{1,

2,

3} , Kenan Sevinç ₁ , Gülben Gürhan Sevinç ₁ , Adam P Cribbs ₄ , Martin Philpott ₄ , Fırat Uyulur ₁ , Tunç Morova ₁ , James E Dunford ₄ , Sencer Göklemez ₁ , Şule Arı ₂ , Udo Oppermann _{4,

5,

6} , Tamer T Önder ₁

Affiliation

Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.

中文翻译：

共激活剂 CBP/EP300 的溴结构域抑制促进细胞重编程。

体细胞类型特异性基因的沉默是重编程中关键但仍知之甚少的步骤。为了揭示维持细胞身份的途径，我们使用染色质因子抑制剂进行了重编程筛选。在这里，我们确定了靶向共激活剂 CREB（环AMP反应元件结合蛋白）结合蛋白（CBP）和 300 kDa E1A 结合蛋白（EP300）的溴结构域的乙酰基赖氨酸竞争性抑制剂作为重编程的有效增强剂。这些抑制剂可加速重编程，在其早期阶段至关重要，当与 DOT1L 抑制相结合时，可以利用 OCT4 和 SOX2 有效衍生人类诱导多能干细胞 (iPSC)。相比之下，CBP/EP300 的催化抑制可阻止 iPSC 形成，这表明不同的共激活子结构域在重编程中具有不同的功能。 CBP/EP300 溴结构域抑制可降低体细胞特异性基因表达、组蛋白 H3 赖氨酸 27 乙酰化 (H3K27Ac) 以及靶启动子和增强子处的染色质可及性。主间充质转录因子 PRRX1 是 CBP/EP300 溴结构域抑制的功能重要靶标之一。总的来说，这些结果表明 CBP/EP300 溴结构域维持细胞类型特异性基因表达并维持细胞身份。

更新日期：2019-05-16

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