Nguyen Thinh T, Savory Joanne G A, Brooke-Bisschop Travis, Ringuette Randy, Foley Tanya, Hess Bradley L, Mulatz Kirk J, Trinkle-Mulcahy Laura, Lohnes David
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
J Biol Chem. 2017 Feb 24;292(8):3389-3399. doi: 10.1074/jbc.M116.752774. Epub 2017 Jan 12.
The packaging of genomic DNA into nucleosomes creates a barrier to transcription that can be relieved through ATP-dependent chromatin remodeling via complexes such as the switch-sucrose non-fermentable (SWI-SNF) chromatin remodeling complex. The SWI-SNF complex remodels chromatin via conformational or positional changes of nucleosomes, thereby altering the access of transcriptional machinery to target genes. The SWI-SNF complex has limited ability to bind to sequence-specific elements, and, therefore, its recruitment to target loci is believed to require interaction with DNA-associated transcription factors. The Cdx family of homeodomain transcript ion factors (Cdx1, Cdx2, and Cdx4) are essential for a number of developmental programs in the mouse. Cdx1 and Cdx2 also regulate intestinal homeostasis throughout life. Although a number of Cdx target genes have been identified, the basis by which Cdx members impact their transcription is poorly understood. We have found that Cdx members interact with the SWI-SNF complex and make direct contact with Brg1, a catalytic member of SWI-SNF. Both Cdx2 and Brg1 co-occupy a number of Cdx target genes, and both factors are necessary for transcriptional regulation of such targets. Finally, Cdx2 and Brg1 occupancy occurs coincident with chromatin remodeling at some of these loci. Taken together, our findings suggest that Cdx transcription factors regulate target gene expression, in part, through recruitment of Brg1-associated SWI-SNF chromatin remodeling activity.
基因组DNA包装成核小体会对转录形成障碍，而通过依赖ATP的染色质重塑，如借助开关-蔗糖不发酵（SWI-SNF）染色质重塑复合体等，可以消除这一障碍。SWI-SNF复合体通过核小体的构象或位置变化重塑染色质，从而改变转录机制对靶基因的可及性。SWI-SNF复合体结合序列特异性元件的能力有限，因此，其募集到靶位点被认为需要与DNA相关转录因子相互作用。同源结构域转录因子Cdx家族（Cdx1、Cdx2和Cdx4）对小鼠的许多发育程序至关重要。Cdx1和Cdx2在整个生命过程中也调节肠道内稳态。尽管已经鉴定出许多Cdx靶基因，但对Cdx成员影响其转录的基础了解甚少。我们发现Cdx成员与SWI-SNF复合体相互作用，并与SWI-SNF的催化成员Brg1直接接触。Cdx2和Brg1共同占据许多Cdx靶基因，并且这两个因子对于此类靶标的转录调控都是必需的。最后，在其中一些位点，Cdx2和Brg1的占据与染色质重塑同时发生。综上所述，我们的研究结果表明，Cdx转录因子部分通过募集与Brg1相关的SWI-SNF染色质重塑活性来调节靶基因表达。
