Abstract
TAL1/SCL is a master regulator of haematopoiesis whose expression promotes opposite outcomes depending on the cell type: differentiation in the erythroid lineage or oncogenesis in the T-cell lineage. Here, we used a combination of ChIP sequencing and gene expression profiling to compare the function of TAL1 in normal erythroid and leukaemic T cells. Analysis of the genome-wide binding properties of TAL1 in these two haematopoietic lineages revealed new insight into the mechanism by which transcription factors select their binding sites in alternate lineages. Our study shows limited overlap in the TAL1-binding profile between the two cell types with an unexpected preference for ETS and RUNX motifs adjacent to E-boxes in the T-cell lineage. Furthermore, we show that TAL1 interacts with RUNX1 and ETS1, and that these transcription factors are critically required for TAL1 binding to genes that modulate T-cell differentiation. Thus, our findings highlight a critical role of the cellular environment in modulating transcription factor binding, and provide insight into the mechanism by which TAL1 inhibits differentiation leading to oncogenesis in the T-cell lineage.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Binding Sites / genetics
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Cell Differentiation / genetics*
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Cell Transformation, Neoplastic / genetics*
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Cells, Cultured
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Chromatin Immunoprecipitation
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism
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Gene Expression Profiling
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Hematopoiesis / genetics*
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Hematopoiesis / physiology
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Humans
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Jurkat Cells
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Leukemia, T-Cell / genetics
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Leukemia, T-Cell / metabolism*
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Microarray Analysis
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Molecular Sequence Data
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Proto-Oncogene Protein c-ets-1 / genetics
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Proto-Oncogene Protein c-ets-1 / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Analysis, DNA
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T-Cell Acute Lymphocytic Leukemia Protein 1
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T-Lymphocytes / cytology
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T-Lymphocytes / metabolism*
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Core Binding Factor Alpha 2 Subunit
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ETS1 protein, human
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins
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RUNX1 protein, human
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T-Cell Acute Lymphocytic Leukemia Protein 1
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TAL1 protein, human