mSin3A regulates murine erythroleukemia cell differentiation through association with the TAL1 (or SCL) transcription factor.
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.
Huang
S
S
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Brandt
S J
SJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C099683:SIN3A transcription factor; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human