Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Cell. 2013 Dec 5;155(6):1380-95. doi: 10.1016/j.cell.2013.11.016.
Transcription factor activity and turnover are functionally linked, but the global patterns by which DNA-bound regulators are eliminated remain poorly understood. We established an assay to define the chromosomal location of DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map described here ties proteolysis in mammalian cells to active enhancers and to promoters of specific gene families. Nuclear-encoded mitochondrial genes in particular correlate with protein elimination, which positively affects their transcription. We show that the nuclear receptor corepressor NCoR1 is a key target of proteolysis and physically interacts with the transcription factor CREB. Proteasome inhibition stabilizes NCoR1 in a site-specific manner and restrains mitochondrial activity by repressing CREB-sensitive genes. In conclusion, this functional map of nuclear proteolysis links chromatin architecture with local protein stability and identifies proteolytic derepression as highly dynamic in regulating the transcription of genes involved in energy metabolism.
转录因子的活性和周转率是功能相关的，但 DNA 结合调控因子被清除的全局模式仍知之甚少。我们建立了一种测定方法，以确定拟通过泛素-蛋白酶体系统降解的与 DNA 相关的蛋白质在染色体上的位置。此处描述的全基因组图谱将哺乳动物细胞中的蛋白水解与活性增强子和特定基因家族的启动子联系起来。特别是核编码的线粒体基因与蛋白消除相关，这对其转录有积极影响。我们表明，核受体共抑制因子 NCoR1 是蛋白水解的关键靶标，并且与转录因子 CREB 物理相互作用。蛋白酶体抑制以特定方式稳定 NCoR1，并通过抑制 CREB 敏感基因来抑制线粒体活性。总之，这种核蛋白水解的功能图谱将染色质结构与局部蛋白质稳定性联系起来，并确定蛋白水解去抑制作为调节与能量代谢相关基因转录的高度动态过程。
