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Molecular and Cellular Biology, March 2000, p. 2248-2259, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

mSin3A Regulates Murine Erythroleukemia Cell Differentiation through Association with the TAL1 (or SCL) Transcription Factor

Suming Huang1 and Stephen J. Brandt1,2,3,4,*

Departments of Medicine1 and Cell Biology2 and Vanderbilt-Ingram Cancer Center,3 Vanderbilt University Medical Center and Department of Veterans Affairs Medical Center,4 Nashville, Tennessee 37232

Received 21 July 1999/Returned for modification 2 September 1999/Accepted 9 December 1999

Activation of the TAL1 (or SCL) gene is the most frequent gain-of-function mutation in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 belongs to the basic helix-loop-helix (HLH) family of transcription factors that bind as heterodimers with the E2A and HEB/HTF4 gene products to a nucleotide sequence motif termed the E-box. Reported to act both as an activator and as a repressor of transcription, the mechanisms underlying TAL1-regulated gene expression are poorly understood. We report here that the corepressor mSin3A is associated with TAL1 in murine erythroleukemia (MEL) and human T-ALL cells. Interaction mapping showed that the basic-HLH domain of TAL1 was both necessary and sufficient for TAL1-mSin3A interaction. TAL1 was found, in addition, to interact with the histone deacetylase HDAC1 in vitro and in vivo, and a specific histone deacetylase inhibitor, trichostatin A (TSA), relieved TAL1-mediated repression of an E-box-containing promoter and a GAL4 reporter linked to a thymidine kinase minimal promoter. Further, TAL1 association with mSin3A and HDAC1 declined during dimethyl sulfoxide-induced differentiation of MEL cells in parallel with a decrease in mSin3A abundance. Finally, TSA had a synergistic effect with enforced TAL1 expression in stimulating MEL cells to differentiate, while constitutive expression of mSin3A inhibited MEL cell differentiation. These results demonstrate that a corepressor complex containing mSin3A and HDAC1 interacts with TAL1 and restricts its function in erythroid differentiation. This also has implications for this transcription factor's actions in leukemogenesis.

* Corresponding author. Mailing address: Division of Hematology-Oncology, Room 547 MRB II, Vanderbilt University Medical Center, Nashville, TN 37232. Phone: (615) 936-1809. Fax: (615) 936-3853. E-mail: stephen.brandt{at}mcmail.vanderbilt.edu.

Molecular and Cellular Biology, March 2000, p. 2248-2259, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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