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Review
. 2016 Oct 3;8(10):a022079.
doi: 10.1101/cshperspect.a022079.

Transcriptional Control by the SMADs

Caroline S Hill  1
Affiliations
Review

Transcriptional Control by the SMADs

Caroline S Hill. Cold Spring Harb Perspect Biol. .

Abstract

The transforming growth factor-β (TGF-β) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of _target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-β family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

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Figures

Figure 1.
Figure 1.
DNA binding by SMAD1 and SMAD3. (A) Schematic showing how a trimer consisting of two SMAD3s and one SMAD4 could bind to direct repeats of SMAD-binding elements (SBEs), such as that found in the JUN enhancer (Wong et al. 1999). (B) Schematic showing how a trimer consisting of two SMAD1s and one SMAD4 could bind to the GGCGCCN5GTCT-binding site together with Schnurri. (Panel based on Gao et al. 2005.) (C) The crystal structure of the SMAD3 MH1 domain interacting with a palindromic GTCTAGAC sequence (PDB code, 1mhd) (Shi et al. 1998). For clarity, only one MH1 domain is shown. The DNA strands are colored in yellow and brown. The key interacting A and G on the yellow strand are colored orange and the key interacting G on the brown strand is colored pink. Amino acids R74, Q76, and K81 are indicated. (D) The crystal structure of the SMAD1 MH1 domain interacting with a palindromic GTCTAGAC sequence (PDB code, 3KMP) (Baburajendran et al. 2010). For clarity, only one MH1 domain is shown. The DNA strands are as in C and amino acids R74, Q76, and K81 are indicated. (E) An overlay of the two structures shown in A and B. To visualize the different positions of the α1 helices, the structures have been rotated ∼20° out of the plane of the paper. (F) A schematic showing the key amino acid–base interactions. The colors are as in C and D. (Panel based on Shi et al. 1998.) (Panels C–E were prepared using PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC.)
Figure 2.
Figure 2.
Examples of different modes of SMAD-mediated transcriptional regulation. (A) Self-enabling (positive). In Xenopus, mixer is a NODAL/activin-induced gene that is induced via a Foxh1–SMAD2–SMAD4 complex. Mixer itself then recruits SMAD2–SMAD4 complexes to the goosecoid enhancer (Germain et al. 2000). (B) Switch enhancer. In pluripotent human embryonic stem cells (ESCs), the TSO complex together with the NuRD complex acts to inhibit transcription of mesendodermal genes and to buffer pluripotency genes. On differentiation to mesendoderm precursor cells, the TSO complex is disrupted and the SMADs bind FOXH1 to activate transcription of mesendodermal genes. (Panel based on Beyer et al. 2013.) (C) Self-enabling (negative). ATF3 is a TGF-β-induced gene that is induced via SMAD3–SMAD4 complexes. ATF3 then cooperates with SMAD3 and SMAD4 to repress transcription of ID1 (Kang et al. 2003). (D) Derepression. SKI and SKIL bind with SMAD4 together with corepressors to SMAD-binding elements (SBEs) to keep SMAD3-dependent genes repressed. On TGF-β/activin/NODAL signaling, RNF111 (Arkadia) is recruited to SKI/SKIL via activated SMAD2/3 to induce rapid degradation of SKI/SKIL. This exposes the SBEs to allow binding of activated SMAD3–SMAD4 complexes for transcriptional activation (Levy et al. 2007).
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