Abstract
Developmental control mechanisms often use multimeric complexes containing transcription factors, coregulators, and additional non-DNA binding components. It is challenging to ascertain how such components contribute to complex function at endogenous loci. We analyzed the function of components of a complex containing master regulators of hematopoiesis (GATA-1 and Scl/TAL1) and the non-DNA binding components ETO2, the LIM domain protein LMO2, and the chromatin looping factor LDB1. Surprisingly, we discovered that ETO2 and LMO2 regulate distinct target-gene ensembles in erythroid cells. ETO2 commonly repressed GATA-1 function via suppressing histone H3 acetylation, although it also regulated methylation of histone H3 at lysine 27 at select loci. Prior studies defined multiple modes by which GATA-1 regulates target genes with or without the coregulator Friend of GATA-1 (FOG-1). LMO2 selectively repressed genes that GATA-1 represses in a FOG-1-independent manner. As LMO2 controls hematopoiesis, its dysregulation is leukemogenic, and its influence on GATA factor function is unknown, this mechanistic link has important biological and pathophysiological implications. The demonstration that ETO2 and LMO2 exert qualitatively distinct functions at endogenous loci illustrates how components of complexes containing master developmental regulators can impart the capacity to regulate unique cohorts of target genes, thereby diversifying complex function.
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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Adaptor Proteins, Signal Transducing
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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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Blotting, Western
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Cells, Cultured
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Chromatin Immunoprecipitation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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GATA1 Transcription Factor / genetics
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GATA1 Transcription Factor / metabolism
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Gene Expression Profiling
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Gene Knockdown Techniques
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Hematopoiesis / genetics*
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LIM Domain Proteins
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Metalloproteins / genetics
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Metalloproteins / metabolism
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Multiprotein Complexes / genetics
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Multiprotein Complexes / physiology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / genetics
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RUNX1 Translocation Partner 1 Protein
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Regulatory Elements, Transcriptional / genetics
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Regulatory Elements, Transcriptional / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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GATA1 Transcription Factor
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GATA1 protein, human
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LDB1 protein, human
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LIM Domain Proteins
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LMO2 protein, human
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Metalloproteins
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Multiprotein Complexes
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Proto-Oncogene Proteins
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RNA, Small Interfering
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RUNX1 Translocation Partner 1 Protein
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RUNX1T1 protein, human
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Transcription Factors
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TAL1 protein, human