Dyer Jamie O, Dutta Arnob, Gogol Madelaine, Weake Vikki M, Dialynas George, Wu Xilan, Seidel Christopher, Zhang Ying, Florens Laurence, Washburn Michael P, Abmayr Susan M, Workman Jerry L
Department of Biology, Rockhurst University, Kansas City, MO 64110, USA.
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
J Mol Biol. 2017 Jun 30;429(13):2093-2107. doi: 10.1016/j.jmb.2016.10.026. Epub 2016 Oct 27.
Mutations that affect myelodysplasia/myeloid leukemia factor (MLF) proteins are associated with leukemia and several other cancers. However, with no strong homology to other proteins of known function, the role of MLF proteins in the cell has remained elusive. Here, we describe a proteomics approach that identifies MLF as a member of a nuclear chaperone complex containing a DnaJ protein, BCL2-associated anthanogene 2, and Hsc70. This complex associates with chromatin and regulates the expression of target genes. The MLF complex is bound to sites of nucleosome depletion and sites containing active chromatin marks (e.g., H3K4me3 and H3K4me1). Hence, MLF binding is enriched at promoters and enhancers. Additionally, the MLF-chaperone complex functions to regulate transcription factor stability, including the RUNX transcription factor involved in hematopoiesis. Although Hsc70 and other co-chaperones have been shown to play a role in nuclear translocation of a variety of proteins including transcription factors, our findings suggest that MLF and the associated co-chaperones play a direct role in modulating gene transcription.
影响骨髓发育异常/髓系白血病因子（MLF）蛋白的突变与白血病及其他几种癌症相关。然而，由于与其他已知功能的蛋白没有很强的同源性，MLF蛋白在细胞中的作用一直难以捉摸。在此，我们描述了一种蛋白质组学方法，该方法鉴定出MLF是一个核伴侣复合体的成员，该复合体包含一个DnaJ蛋白、BCL2相关抗凋亡蛋白2和Hsc70。这个复合体与染色质结合并调节靶基因的表达。MLF复合体与核小体缺失位点以及含有活性染色质标记（如H3K4me3和H3K4me1）的位点结合。因此，MLF结合在启动子和增强子处富集。此外，MLF伴侣复合体发挥作用调节转录因子稳定性，包括参与造血的RUNX转录因子。尽管Hsc70和其他共伴侣已被证明在包括转录因子在内的多种蛋白的核转运中发挥作用，但我们的研究结果表明，MLF和相关的共伴侣在调节基因转录中起直接作用。
