Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex
| Autor: | Joël Vandekerckhove, Christine Michiels, Griet Verstappen, Eric Bellefroid, Leonardus Van Grunsven, Tom Van de Putte, Jacob Souopgui, Danny Huylebroeck, Jozef Van Damme |
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| Přispěvatelé: | Liver Cell Biology, Cell Biology and Histology |
| Předmět: |
Embryo
Nonmammalian HISTONE DEACETYLASE Xenopus DNA-BINDING Mutant Mowat-Wilson Syndrome Nerve Tissue Proteins RNA-binding protein SYNDROME PHENOTYPE Autoantigens Histone Deacetylases Zfhx1b Cell Line chromatin modification Protein structure MISSENSE MUTATION NuRD Intellectual Disability E-CADHERIN Genetics Animals Humans Abnormalities Multiple RBBP4 CtBP Molecular Biology Psychological repression Genetics (clinical) Adenosine Triphosphatases SMAD-INTERACTING PROTEIN-1 biology sip1 DNA Helicases RNA-Binding Proteins Syndrome General Medicine HIRSCHSPRUNG-DISEASE Cadherins biology.organism_classification Mi-2/NuRD complex Protein Structure Tertiary TRANSCRIPTIONAL REPRESSION XENOPUS MENTAL RETARDATION SYNDROME Corepressor Mi-2 Nucleosome Remodeling and Deacetylase Complex |
| Zdroj: | Vrije Universiteit Brussel HUMAN MOLECULAR GENETICS |
| ISSN: | 0964-6906 |
| Popis: | 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-2 beta 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. |
| Databáze: | OpenAIRE |
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