Abstract
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.
Highlights
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
Using a quantitative affinity purification/MS approach based on stable isotope labeling by amino acids in culture (SILAC) [31], we found that Cdx2 associates with multiple members of the Brg1-containing SWI-SNF complex in HEK293 cells
We further found that Cdx2 and Brg1 associated in vitro, suggesting direct interaction, and that both factors co-occupied a number of Cdx target genes
Summary
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. Our findings suggest that Cdx transcription factors regulate target gene expression, in part, through recruitment of Brg1-associated SWI-SNF chromatin remodeling activity. The three members of this family (Cdx, Cdx, and Cdx4) are co-expressed in the caudal embryo in all three germ layers commencing at mid-gastrulation and play overlapping roles in a number of developmental programs, including axial elongation, endoderm specification, and anterior-posterior vertebral patterning [1,2,3,4,5,6]. Alteration of the chromatin structure by ATP-dependent remodeling complexes can alleviate these constraints, and such complexes play important roles in the transcriptional regulation of many eukaryotic genes Such complexes include the switch-sucrose non-fermentable (SWI-SNF) chromatin-remodeling complex (16, 20 –22), which remodels the chromatin structure via conformational or positional changes of nucleosomes [23, 24]. These findings suggest that Cdx members modulate target gene transcription, at least in part, through recruitment of SWI-SNF-mediated chromatin remodeling
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