Signaling Pathways Associated with Chromatin Remodeling
Numerous signaling cascades converge on the nucleus during development to direct chromatin remodeling that influences transcriptional regulation. For example, proper TGFβ signaling gradients are essential for cellular viability and differentiation. Activation of TGFβ receptors located at the cell surface catalyzes a phosphorylation cascade that leads to SMAD protein interactions in the cytoplasm and their subsequent relocation to the nucleus. Interestingly, high cell density of various cell lines prevented SMAD translocation to the nucleus in vitro, suggesting extrinsic factors in addition to morphogen gradients that may contribute to TGFβ signaling.
The SMAD1/5/8 complex is activated via BMP GDF ligands, while Activin/NODAL associated SMAD2/3 complex. Once transported inside the nucleus, the SMAD complex interacts with additional transcription factors to bind the SMAD DNA binding element and activate target gene expression. Work in X. laevis showed that the SMAD2/3 complex interacts with Mix and FoxO family transcription factors to activate genes such as GSC and p21. This complex activates gene expression by recruiting the HAT p300 and Brg1 to target loci. The SMAD2/3 complex also represses gene expression when it associates with ATF3, suggesting it has various roles in gene regulation. Recent ChIP-Seq studies also showed that SMAD1 binding overlapped with GATA1/2 in K562 cells, and could be re-directed to new binding sites with ectopic expression of CEBPα. Ectopic expression of MyoD in mESCs also provided evidence that SMAD3 can be re-directed to new binding sites by this TF. Collectively, these studies suggest that master TF regulators of cell fate can direct SMAD binding which putatively induces chromatin remodeling and gene activation.
WNT/β catenin signaling has also been show to direct chromatin remodeling. WNT ligands bind to Frizzeled and LRP receptors on the cell surface, allows β catenin’s translocation to the nucleus where it interacts with TCF/LEF transcription factors to promote gene activation. In addition to an overlap between GATA1/2 and SMAD1 previously mentioned, Trompouki and colleagues also found that TCF7L2 binding overlapped with SMAD1/GATA1/2 binding, suggesting an overlap in WNT and BMP signaling pathways. In some scenarios, the C terminus of β catenin directly interacts with the HMTs MLL1/MLL2 to stimulate H3K4 methylation, which leads to expression of genes such as c-Myc. Modulation of these pathways through extracellular binding of ligands therefore represents a mechanism that links developmental signaling cues with nuclear remodeling.