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The structural basis for the oligomerization of the N-terminal domain of SATB1.

Wang Z, Yang X, Chu X, Zhang J, Zhou H, Shen Y, Long J - Nucleic Acids Res. (2012)

Bottom Line: Our results also reveal that SATB1 can form a tetramer through its N-terminal domain.Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets.Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.

ABSTRACT
Special AT-rich sequence-binding protein 1 (SATB1) is a global chromatin organizer and gene expression regulator essential for T-cell development and breast cancer tumor growth and metastasis. The oligomerization of the N-terminal domain of SATB1 is critical for its biological function. We determined the crystal structure of the N-terminal domain of SATB1. Surprisingly, this domain resembles a ubiquitin domain instead of the previously proposed PDZ domain. Our results also reveal that SATB1 can form a tetramer through its N-terminal domain. The tetramerization of SATB1 plays an essential role in its binding to highly specialized DNA sequences. Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets. Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.

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Model of SATB1-mediated transcriptional regulation. (A) Schematic showing SATB1 assembles into a tetramer by oligomerization of its N-terminal ULD domain. (B and C) Schematic representation of a possible model for SATB1 oligomer-mediated transcriptional regulation. The SATB1 dimer or tetramer may regulate gene expression by recognizing specific DNA sequences in the promoter regions of various genes (B), and the SATB1 tetramer may organize higher-order chromatin architecture to coordinately regulate gene expression over long distances by anchoring specialized DNA sequences in close proximity and recruiting various chromatin remodeling factors (bottom).
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gkr1284-F5: Model of SATB1-mediated transcriptional regulation. (A) Schematic showing SATB1 assembles into a tetramer by oligomerization of its N-terminal ULD domain. (B and C) Schematic representation of a possible model for SATB1 oligomer-mediated transcriptional regulation. The SATB1 dimer or tetramer may regulate gene expression by recognizing specific DNA sequences in the promoter regions of various genes (B), and the SATB1 tetramer may organize higher-order chromatin architecture to coordinately regulate gene expression over long distances by anchoring specialized DNA sequences in close proximity and recruiting various chromatin remodeling factors (bottom).

Mentions: Oligomerization of SATB1 plays a very important role in DNA binding and has been implicated in gene regulation by SATB1. The structure of the SATB1 ULD domain reported here provides the molecular basis for how the ULD domain mediated the oligomerization state of SATB1. SATB1 assembles into a tetramer in vitro (Figure 5A), and the tetramerization of SATB1 is essential for recognizing specific DNA sequences (such as multiple AT-rich DNA fragments). Thus, SATB1 may regulate gene expression directly by binding to various promoters and upstream regions and thereby influencing promoter activity (Figure 5B). This local gene regulation model is consistent with experimental observations that SATB1 directly regulates the expression of a number of genes, including globin, interleukin-2, interleukin-2 receptor α and interleukin-5, by recruiting either coactivators or corepressors (5–8). Furthermore, we showed that the SATB1 tetramer can simultaneously bind to two DNA segments, and thus the tetramerization of SATB1 may organize high-order chromatin architecture by anchoring specialized DNA sequences in close proximity and recruiting various chromatin remodeling factors to coordinately regulate gene expression over long distances (Figure 5C). This long-range gene regulation model is also consistent with the observations that SATB1 regulates the coordinated expression of genes located both at the 200-kb T-helper 2 cytokine locus (10) and at the 300-kb major histocompatibility Class I locus (11), and that it reprograms chromatin organization and the transcriptional profiles of breast tumors to promote growth and metastasis (12,31,32).Figure 5.


The structural basis for the oligomerization of the N-terminal domain of SATB1.

Wang Z, Yang X, Chu X, Zhang J, Zhou H, Shen Y, Long J - Nucleic Acids Res. (2012)

Model of SATB1-mediated transcriptional regulation. (A) Schematic showing SATB1 assembles into a tetramer by oligomerization of its N-terminal ULD domain. (B and C) Schematic representation of a possible model for SATB1 oligomer-mediated transcriptional regulation. The SATB1 dimer or tetramer may regulate gene expression by recognizing specific DNA sequences in the promoter regions of various genes (B), and the SATB1 tetramer may organize higher-order chromatin architecture to coordinately regulate gene expression over long distances by anchoring specialized DNA sequences in close proximity and recruiting various chromatin remodeling factors (bottom).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351170&req=5

gkr1284-F5: Model of SATB1-mediated transcriptional regulation. (A) Schematic showing SATB1 assembles into a tetramer by oligomerization of its N-terminal ULD domain. (B and C) Schematic representation of a possible model for SATB1 oligomer-mediated transcriptional regulation. The SATB1 dimer or tetramer may regulate gene expression by recognizing specific DNA sequences in the promoter regions of various genes (B), and the SATB1 tetramer may organize higher-order chromatin architecture to coordinately regulate gene expression over long distances by anchoring specialized DNA sequences in close proximity and recruiting various chromatin remodeling factors (bottom).
Mentions: Oligomerization of SATB1 plays a very important role in DNA binding and has been implicated in gene regulation by SATB1. The structure of the SATB1 ULD domain reported here provides the molecular basis for how the ULD domain mediated the oligomerization state of SATB1. SATB1 assembles into a tetramer in vitro (Figure 5A), and the tetramerization of SATB1 is essential for recognizing specific DNA sequences (such as multiple AT-rich DNA fragments). Thus, SATB1 may regulate gene expression directly by binding to various promoters and upstream regions and thereby influencing promoter activity (Figure 5B). This local gene regulation model is consistent with experimental observations that SATB1 directly regulates the expression of a number of genes, including globin, interleukin-2, interleukin-2 receptor α and interleukin-5, by recruiting either coactivators or corepressors (5–8). Furthermore, we showed that the SATB1 tetramer can simultaneously bind to two DNA segments, and thus the tetramerization of SATB1 may organize high-order chromatin architecture by anchoring specialized DNA sequences in close proximity and recruiting various chromatin remodeling factors to coordinately regulate gene expression over long distances (Figure 5C). This long-range gene regulation model is also consistent with the observations that SATB1 regulates the coordinated expression of genes located both at the 200-kb T-helper 2 cytokine locus (10) and at the 300-kb major histocompatibility Class I locus (11), and that it reprograms chromatin organization and the transcriptional profiles of breast tumors to promote growth and metastasis (12,31,32).Figure 5.

Bottom Line: Our results also reveal that SATB1 can form a tetramer through its N-terminal domain.Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets.Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.

ABSTRACT
Special AT-rich sequence-binding protein 1 (SATB1) is a global chromatin organizer and gene expression regulator essential for T-cell development and breast cancer tumor growth and metastasis. The oligomerization of the N-terminal domain of SATB1 is critical for its biological function. We determined the crystal structure of the N-terminal domain of SATB1. Surprisingly, this domain resembles a ubiquitin domain instead of the previously proposed PDZ domain. Our results also reveal that SATB1 can form a tetramer through its N-terminal domain. The tetramerization of SATB1 plays an essential role in its binding to highly specialized DNA sequences. Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets. Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.

Show MeSH
Related in: MedlinePlus