Kaiso Directs the Transcriptional Corepressor MTG16 to the Kaiso Binding Site in Target Promoters

Caitlyn W. Barrett, J. Joshua Smith, Lauren C. Lu, Nicholas Markham, Kristy R. Stengel, Sarah P. Short, Baolin Zhang, Aubrey A. Hunt, Barbara M. Fingleton, Robert H. Carnahan, Michael E. Engel, Xi Chen, R. Daniel Beauchamp, Keith T. Wilson, Scott W. Hiebert, Albert B. Reynolds, Christopher S. Williams

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Myeloid translocation genes (MTGs) are transcriptional corepressors originally identified in acute myelogenous leukemia that have recently been linked to epithelial malignancy with non-synonymous mutations identified in both MTG8 and MTG16 in colon, breast, and lung carcinoma in addition to functioning as negative regulators of WNT and Notch signaling. A yeast two-hybrid approach was used to discover novel MTG binding partners. This screen identified the Zinc fingers, C2H2 and BTB domain containing (ZBTB) family members ZBTB4 and ZBTB38 as MTG16 interacting proteins. ZBTB4 is downregulated in breast cancer and modulates p53 responses. Because ZBTB33 (Kaiso), like MTG16, modulates Wnt signaling at the level of TCF4, and its deletion suppresses intestinal tumorigenesis in the ApcMin mouse, we determined that Kaiso also interacted with MTG16 to modulate transcription. The zinc finger domains of Kaiso as well as ZBTB4 and ZBTB38 bound MTG16 and the association with Kaiso was confirmed using co-immunoprecipitation. MTG family members were required to efficiently repress both a heterologous reporter construct containing Kaiso binding sites (4×KBS) and the known Kaiso target, Matrix metalloproteinase-7 (MMP-7/Matrilysin). Moreover, chromatin immunoprecipitation studies placed MTG16 in a complex occupying the Kaiso binding site on the MMP-7 promoter. The presence of MTG16 in this complex, and its contributions to transcriptional repression both required Kaiso binding to its binding site on DNA, establishing MTG16-Kaiso binding as functionally relevant in Kaiso-dependent transcriptional repression. Examination of a large multi-stage CRC expression array dataset revealed patterns of Kaiso, MTG16, and MMP-7 expression supporting the hypothesis that loss of either Kaiso or MTG16 can de-regulate a target promoter such as that of MMP-7. These findings provide new insights into the mechanisms of transcriptional control by ZBTB family members and broaden the scope of co-repressor functions for the MTG family, suggesting coordinate regulation of transcription by Kaiso/MTG complexes in cancer.

Original languageEnglish (US)
Article numbere51205
JournalPLoS One
Volume7
Issue number12
DOIs
StatePublished - Dec 12 2012
Externally publishedYes

Fingerprint

matrilysin
Co-Repressor Proteins
binding sites
Matrix Metalloproteinases
Genes
Binding Sites
promoter regions
Matrix Metalloproteinase 7
Transcription
zinc finger motif
Zinc
genes
Breast Neoplasms
transcription (genetics)
Chromatin Immunoprecipitation
Zinc Fingers
Immunoprecipitation
Acute Myeloid Leukemia
Yeast
Chromatin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Barrett, C. W., Smith, J. J., Lu, L. C., Markham, N., Stengel, K. R., Short, S. P., ... Williams, C. S. (2012). Kaiso Directs the Transcriptional Corepressor MTG16 to the Kaiso Binding Site in Target Promoters. PLoS One, 7(12), [e51205]. https://doi.org/10.1371/journal.pone.0051205

Kaiso Directs the Transcriptional Corepressor MTG16 to the Kaiso Binding Site in Target Promoters. / Barrett, Caitlyn W.; Smith, J. Joshua; Lu, Lauren C.; Markham, Nicholas; Stengel, Kristy R.; Short, Sarah P.; Zhang, Baolin; Hunt, Aubrey A.; Fingleton, Barbara M.; Carnahan, Robert H.; Engel, Michael E.; Chen, Xi; Beauchamp, R. Daniel; Wilson, Keith T.; Hiebert, Scott W.; Reynolds, Albert B.; Williams, Christopher S.

In: PLoS One, Vol. 7, No. 12, e51205, 12.12.2012.

Research output: Contribution to journalArticle

Barrett, CW, Smith, JJ, Lu, LC, Markham, N, Stengel, KR, Short, SP, Zhang, B, Hunt, AA, Fingleton, BM, Carnahan, RH, Engel, ME, Chen, X, Beauchamp, RD, Wilson, KT, Hiebert, SW, Reynolds, AB & Williams, CS 2012, 'Kaiso Directs the Transcriptional Corepressor MTG16 to the Kaiso Binding Site in Target Promoters', PLoS One, vol. 7, no. 12, e51205. https://doi.org/10.1371/journal.pone.0051205
Barrett, Caitlyn W. ; Smith, J. Joshua ; Lu, Lauren C. ; Markham, Nicholas ; Stengel, Kristy R. ; Short, Sarah P. ; Zhang, Baolin ; Hunt, Aubrey A. ; Fingleton, Barbara M. ; Carnahan, Robert H. ; Engel, Michael E. ; Chen, Xi ; Beauchamp, R. Daniel ; Wilson, Keith T. ; Hiebert, Scott W. ; Reynolds, Albert B. ; Williams, Christopher S. / Kaiso Directs the Transcriptional Corepressor MTG16 to the Kaiso Binding Site in Target Promoters. In: PLoS One. 2012 ; Vol. 7, No. 12.
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abstract = "Myeloid translocation genes (MTGs) are transcriptional corepressors originally identified in acute myelogenous leukemia that have recently been linked to epithelial malignancy with non-synonymous mutations identified in both MTG8 and MTG16 in colon, breast, and lung carcinoma in addition to functioning as negative regulators of WNT and Notch signaling. A yeast two-hybrid approach was used to discover novel MTG binding partners. This screen identified the Zinc fingers, C2H2 and BTB domain containing (ZBTB) family members ZBTB4 and ZBTB38 as MTG16 interacting proteins. ZBTB4 is downregulated in breast cancer and modulates p53 responses. Because ZBTB33 (Kaiso), like MTG16, modulates Wnt signaling at the level of TCF4, and its deletion suppresses intestinal tumorigenesis in the ApcMin mouse, we determined that Kaiso also interacted with MTG16 to modulate transcription. The zinc finger domains of Kaiso as well as ZBTB4 and ZBTB38 bound MTG16 and the association with Kaiso was confirmed using co-immunoprecipitation. MTG family members were required to efficiently repress both a heterologous reporter construct containing Kaiso binding sites (4×KBS) and the known Kaiso target, Matrix metalloproteinase-7 (MMP-7/Matrilysin). Moreover, chromatin immunoprecipitation studies placed MTG16 in a complex occupying the Kaiso binding site on the MMP-7 promoter. The presence of MTG16 in this complex, and its contributions to transcriptional repression both required Kaiso binding to its binding site on DNA, establishing MTG16-Kaiso binding as functionally relevant in Kaiso-dependent transcriptional repression. Examination of a large multi-stage CRC expression array dataset revealed patterns of Kaiso, MTG16, and MMP-7 expression supporting the hypothesis that loss of either Kaiso or MTG16 can de-regulate a target promoter such as that of MMP-7. These findings provide new insights into the mechanisms of transcriptional control by ZBTB family members and broaden the scope of co-repressor functions for the MTG family, suggesting coordinate regulation of transcription by Kaiso/MTG complexes in cancer.",
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AU - Barrett, Caitlyn W.

AU - Smith, J. Joshua

AU - Lu, Lauren C.

AU - Markham, Nicholas

AU - Stengel, Kristy R.

AU - Short, Sarah P.

AU - Zhang, Baolin

AU - Hunt, Aubrey A.

AU - Fingleton, Barbara M.

AU - Carnahan, Robert H.

AU - Engel, Michael E.

AU - Chen, Xi

AU - Beauchamp, R. Daniel

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