Abstract
Nodal signaling, mediated through SMAD transcription factors, is necessary for pluripotency maintenance and endoderm commitment. We identified a new motif, termed SMAD complex-associated (SCA), that is bound by SMAD2/3/4 and FOXH1 in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that two basic helix-loop-helix (bHLH) proteins-HEB and E2A-bind the SCA motif at regions overlapping SMAD2/3 and FOXH1. Furthermore, we show that HEB and E2A associate with SMAD2/3 and FOXH1, suggesting they form a complex at critical target regions. This association is biologically important, as E2A is critical for mesendoderm specification, gastrulation, and Nodal signal transduction in Xenopus tropicalis embryos. Taken together, E proteins are novel Nodal signaling cofactors that associate with SMAD2/3 and FOXH1 and are necessary for mesendoderm differentiation.
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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Amino Acid Motifs
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Animals
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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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Cell Line
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Chromatin Immunoprecipitation
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Embryonic Stem Cells
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Endoderm / metabolism
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gastrulation / genetics
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Gene Expression Regulation, Developmental* / genetics
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High-Throughput Nucleotide Sequencing
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Humans
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Left-Right Determination Factors / metabolism
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Protein Binding
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Signal Transduction
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Smad Proteins, Receptor-Regulated / chemistry
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Smad Proteins, Receptor-Regulated / genetics
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Smad Proteins, Receptor-Regulated / metabolism*
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Xenopus / embryology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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FOXH1 protein, human
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Forkhead Transcription Factors
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Left-Right Determination Factors
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Smad Proteins, Receptor-Regulated
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TCF3 protein, human
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TCF12 protein, human