Brd4-Brd2 isoform switching coordinates pluripotent exit and Smad2-dependent lineage specification.
Brd4-Brd2 isoform switching coordinates pluripotent exit and Smad2-dependent lineage specification.
复制标题
DOI：
10.15252/embr.201643534
复制
发表时间：
2017-07
期刊：
影响因子：
7.7
通讯作者：
Findlay GM
中科院分区：
文献类型：
--
作者：
Fernandez-Alonso R;Davidson L;Hukelmann J;Zengerle M;Prescott AR;Lamond A;Ciulli A;Sapkota GP;Findlay GM
多能干细胞（PSC）具有巨大的临床潜力，因为它们具有分化成完全特化组织的能力，如胰腺、肝脏、神经元和心肌。然而，协调多能退出与谱系特异性的分子机制仍然知之甚少。为了解决这个问题，我们进行了小分子筛选，系统地鉴定了 Smad2 信号网络的新型调节因子，Smad2 信号网络是 PSC 命运的关键决定因素。我们揭示了 BET 家族溴结构域蛋白在 Smad2 激活中的重要功能，与 Brd4 在多能性维持中的作用不同。从机制上讲，BET 蛋白特异性地与 Nodal 基因调控元件 (NRE) 结合，以促进 Nodal 信号传导和 Smad2 发育反应。在多能细胞中，Brd2-Brd4 占据 NRE，但多能基因表达只需要 Brd4。 Brd4 下调促进多能退出并增强 Brd2 NRE 占用，从而揭示 Brd2 在分化的 Nodal-Smad2 信号传导中的特定功能。因此，NRE 上不同的 BET 功能和 Brd4-Brd2 同种型转换协调多能退出与谱系规范。
Pluripotent stem cells (PSCs) hold great clinical potential, as they possess the capacity to differentiate into fully specialised tissues such as pancreas, liver, neurons and cardiac muscle. However, the molecular mechanisms that coordinate pluripotent exit with lineage specification remain poorly understood. To address this question, we perform a small molecule screen to systematically identify novel regulators of the Smad2 signalling network, a key determinant of PSC fate. We reveal an essential function for BET family bromodomain proteins in Smad2 activation, distinct from the role of Brd4 in pluripotency maintenance. Mechanistically, BET proteins specifically engage Nodal gene regulatory elements (NREs) to promote Nodal signalling and Smad2 developmental responses. In pluripotent cells, Brd2‐Brd4 occupy NREs, but only Brd4 is required for pluripotency gene expression. Brd4 downregulation facilitates pluripotent exit and drives enhanced Brd2 NRE occupancy, thereby unveiling a specific function for Brd2 in differentiative Nodal‐Smad2 signalling. Therefore, distinct BET functionalities and Brd4‐Brd2 isoform switching at NREs coordinate pluripotent exit with lineage specification.