Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex
Copyright policy )Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex
Mutations in ZFHX1B cause Mowat-Wilson syndrome (MWS) but the precise mechanisms underlying the aberrant functions of mutant ZFHX1B proteins (also named Smad-interacting protein-1, SIP1) in patients are unknown. Using mass spectrometry analysis, we identified subunits of the NuRD corepressor complex in affinity-purified Zfhx1b complexes. We find that Zfhx1b associates with NuRD through its N-terminal domain, which contains a previously postulated NuRD interacting motif. Interestingly, this motif is substituted by an unrelated sequence in a recently described MWS patient. We show here that such aberrant ZFHX1B protein is unable to recruit NuRD subunits and displays reduced transcriptional repression activity on the XBMP4 gene promoter, a target of Zfhx1b. We further demonstrate that the NuRD component Mi-2beta is involved in repression of the Zfhx1b target gene E-cadherin as well as in Zfhx1b-induced neural induction in animal caps from Xenopus embryos. Thus, NuRD and Zfhx1b functionally interact, and defective NuRD recruitment by mutant human ZFHX1B can be a MWS-causing mechanism. This is the first study providing mechanistic insight into the aberrant function of a single domain of the multi-domain protein ZFHX1B/SIP1 in human disease.
- Vrije Universiteit Brussel Belgium
- Université Libre de Bruxelles Belgium
- Ghent University Belgium
- Medical Research Council United Kingdom
- Katholieke Universiteit Leuven Belgium
HISTONE DEACETYLASE, Embryo, Nonmammalian, Mental Retardation -- metabolism, Xenopus, Nerve Tissue Proteins -- genetics, SYNDROME PHENOTYPE, Autoantigens, Zfhx1b, chromatin modification, Autoantigens -- metabolism, CtBP, Adenosine Triphosphatases, sip1, RNA-Binding Proteins, Syndrome, Sciences bio-médicales et agricoles, RNA-Binding Proteins -- metabolism, Cadherins, Embryo, Abnormalities, MENTAL RETARDATION SYNDROME, Nonmammalian -- metabolism, RNA-Binding Proteins -- isolation & purification, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Protein Structure, DNA-BINDING, Mowat-Wilson Syndrome, Nerve Tissue Proteins, Histone Deacetylases, DNA Helicases -- metabolism, Cell Line, MISSENSE MUTATION, NuRD, Intellectual Disability, E-CADHERIN, Adenosine Triphosphatases -- metabolism, Nerve Tissue Proteins -- metabolism, Animals, Humans, Abnormalities, Multiple, Multiple -- metabolism, RNA-Binding Proteins -- genetics, Nerve Tissue Proteins -- isolation & purification, SMAD-INTERACTING PROTEIN-1, DNA Helicases, RNA-Binding Proteins -- chemistry, HIRSCHSPRUNG-DISEASE, Protein Structure, Tertiary, Nerve Tissue Proteins -- chemistry, TRANSCRIPTIONAL REPRESSION, XENOPUS, Cadherins -- metabolism, Histone Deacetylases -- metabolism, Tertiary
HISTONE DEACETYLASE, Embryo, Nonmammalian, Mental Retardation -- metabolism, Xenopus, Nerve Tissue Proteins -- genetics, SYNDROME PHENOTYPE, Autoantigens, Zfhx1b, chromatin modification, Autoantigens -- metabolism, CtBP, Adenosine Triphosphatases, sip1, RNA-Binding Proteins, Syndrome, Sciences bio-médicales et agricoles, RNA-Binding Proteins -- metabolism, Cadherins, Embryo, Abnormalities, MENTAL RETARDATION SYNDROME, Nonmammalian -- metabolism, RNA-Binding Proteins -- isolation & purification, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Protein Structure, DNA-BINDING, Mowat-Wilson Syndrome, Nerve Tissue Proteins, Histone Deacetylases, DNA Helicases -- metabolism, Cell Line, MISSENSE MUTATION, NuRD, Intellectual Disability, E-CADHERIN, Adenosine Triphosphatases -- metabolism, Nerve Tissue Proteins -- metabolism, Animals, Humans, Abnormalities, Multiple, Multiple -- metabolism, RNA-Binding Proteins -- genetics, Nerve Tissue Proteins -- isolation & purification, SMAD-INTERACTING PROTEIN-1, DNA Helicases, RNA-Binding Proteins -- chemistry, HIRSCHSPRUNG-DISEASE, Protein Structure, Tertiary, Nerve Tissue Proteins -- chemistry, TRANSCRIPTIONAL REPRESSION, XENOPUS, Cadherins -- metabolism, Histone Deacetylases -- metabolism, Tertiary
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