McKenna Brian, Guo Min, Reynolds Albert, Hara Manami, Stein Roland
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cell Rep. 2015 Mar 31;10(12):2032-42. doi: 10.1016/j.celrep.2015.02.054. Epub 2015 Mar 19.
Pdx1 is a transcription factor of fundamental importance to pancreas formation and adult islet β cell function. However, little is known about the positive- and negative-acting coregulators recruited to mediate transcriptional control. Here, we isolated numerous Pdx1-interacting factors possessing a wide range of cellular functions linked with this protein, including, but not limited to, coregulators associated with transcriptional activation and repression, DNA damage response, and DNA replication. Because chromatin remodeling activities are essential to developmental lineage decisions and adult cell function, our analysis focused on investigating the influence of the Swi/Snf chromatin remodeler on Pdx1 action. The two mutually exclusive and indispensable Swi/Snf core ATPase subunits, Brg1 and Brm, distinctly affected target gene expression in β cells. Furthermore, physiological and pathophysiological conditions dynamically regulated Pdx1 binding to these Swi/Snf complexes in vivo. We discuss how context-dependent recruitment of coregulatory complexes by Pdx1 could impact pancreas cell development and adult islet β cell activity.
Pdx1是一种对胰腺形成和成年胰岛β细胞功能至关重要的转录因子。然而，对于为介导转录控制而募集的正负调节共激活因子，我们却知之甚少。在此，我们分离出了众多与Pdx1相互作用的因子，这些因子具有与该蛋白相关的广泛细胞功能，包括但不限于与转录激活和抑制、DNA损伤反应及DNA复制相关的共调节因子。由于染色质重塑活动对于发育谱系决定和成年细胞功能至关重要，我们的分析集中于研究Swi/Snf染色质重塑因子对Pdx1作用的影响。两种相互排斥且不可或缺的Swi/Snf核心ATP酶亚基，即Brg1和Brm，对β细胞中的靶基因表达有着截然不同的影响。此外，生理和病理生理条件在体内动态调节Pdx1与这些Swi/Snf复合物的结合。我们讨论了Pdx1对共调节复合物的背景依赖性募集如何影响胰腺细胞发育和成年胰岛β细胞活性。
