Abstract
Hairy/Enhancer of split 1 (Hes1) is a mammalian transcriptional repressor that plays crucial roles in the regulation of several developmental processes, including neuronal differentiation. The aim of this study was to elucidate the molecular mechanisms that regulate the transcription repression activity of Hes1. It is shown here that Hes1 associates with the nuclear matrix, the ribonucleoprotein network of the nucleus that plays important roles in transcriptional regulation. Nuclear matrix binding is mediated by the same Hes1 C-terminal domain that is also required for transcriptional repression. This domain contains the WRPW motif that acts as a binding site for the transcriptional corepressor Groucho, which also localizes to the nuclear matrix. Both the nuclear matrix association and transcription repression activity of Hes1 are inhibited by deletion of the WRPW motif, indicating that Groucho acts as a transcriptional corepressor for Hes1. This corepressor role is not modulated by the Groucho-related gene product Grg5. In contrast, the Runt-related protein RUNX2, which localizes to the nuclear matrix and interacts with Groucho and Hes1, can inhibit both the Groucho.Hes1 interaction and the transcription repression ability of Hes1. Together, these observations suggest that transcriptional repression by Hes1 requires interactions with Groucho at the nuclear matrix and that RUNX proteins act as negative regulators of the repressive activity of Groucho.Hes1 complexes.
Highlights
In the mammalian central nervous system, progenitor cells located in the ventricular zone of the neural tube undergo proliferation and differentiate into neurons in response to intrinsic and extrinsic cues
Hairy/Enhancer of split 1 (Hes1) Interacts with transducin-like Enhancer of split (TLE) in a WRPW Motif-dependent Way— Hes1 is coexpressed with TLE proteins in a number of mammalian cell types (14, 24 –26, 29) and physically interacts with TLE1 and TLE2 in vitro [20, 28, 29]
Stration that Hes1 associates with the nuclear matrix, a nuclear compartment where TLE and RUNX proteins, both of which interact with Hes1, are found [45,46,47,48]
Summary
In the mammalian central nervous system, progenitor cells located in the ventricular zone of the neural tube undergo proliferation and differentiate into neurons in response to intrinsic and extrinsic cues. Mutations that inhibit the Groucho1⁄7Hes interaction interfere with the ability of Drosophila Hes proteins to repress transcription, suggesting that Groucho acts a transcriptional corepressor for these factors [11, 20, 21] These findings first raised the possibility that mammalian homologs of Drosophila Groucho, designated as transducin-like Enhancer of split (TLE) or Groucho-related genes (Grg) 1 through 4 (hereafter referred to as TLE1– 4) [22, 23], may be involved in transcriptional repression by Hes. Taken together with the demonstration that TLE proteins provide a transcriptional corepressor function to a number of different DNA-binding factors (30 –33), these observations suggest that transcriptional repression by Hes is regulated by interactions with TLE family members. It remains to be determined, whether Hes and TLE proteins functionally interact in vivo and, if so, how their transcriptional functions are regulated
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