Repression of Transcription by WT1-BASP1 Requires the Myristoylation of BASP1 and the PIP2-Dependent Recruitment of Histone Deacetylase

• Published in: Cell reports (Cambridge) 2012-09, Vol.2 (3), p.462-469
• Main Authors: Toska, Eneda, Campbell, Hayley A., Shandilya, Jayasha, Goodfellow, Sarah J., Shore, Paul, Medler, Kathryn F., Roberts, Stefan G.E.
• Format: Article
• Language: English
• Subjects: Cell Nucleus - genetics; Cell Nucleus - metabolism; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Humans; K562 Cells; Lipoylation - physiology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Phosphatidylinositol 4,5-Diphosphate - genetics; Phosphatidylinositol 4,5-Diphosphate - metabolism; Promoter Regions, Genetic - physiology; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transcription, Genetic - physiology; WT1 Proteins - genetics; WT1 Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.08.005

The Wilms' tumor 1 protein WT1 is a transcriptional regulator that is involved in cell growth and differentiation. The transcriptional corepressor BASP1 interacts with WT1 and converts WT1 from a transcriptional activator to a repressor. Here, we demonstrate that the N-terminal myristoylation of BASP1 is required in order to elicit transcriptional repression at WT1 target genes. We show that myristoylated BASP1 binds to nuclear PIP2, which leads to the recruitment of PIP2 to the promoter regions of WT1-dependent target genes. BASP1's myristoylation and association with PIP2 are required for the interaction of BASP1 with HDAC1, which mediates the recruitment of HDAC1 to the promoter and elicits transcriptional repression. Our findings uncover a role for myristoylation in transcription, as well as a critical function for PIP2 in gene-specific transcriptional repression through the recruitment of histone deacetylase. [Display omitted] ► Myristoylation of BASP1 is required for its function as a transcriptional repressor ► BASP1 myristoylation facilitates its interaction with nuclear PIP2 ► Myristoylation of BASP1 recruits HDAC1 to gene promoters through PIP2 Protein myristoylation is traditionally associated with membrane targeting and signal transduction processes. Here, Roberts and colleagues demonstrate that the N-terminal myristoylation of the Wilms' tumor suppressor protein cofactor BASP1 plays a direct role in the regulation of transcription. Myristoylation of BASP1 promotes its interaction with the phospholipid PIP2 and is required in order to recruit histone deacetylase and elicit transcriptional repression. These findings uncover a role for myristoylation in transcription and demonstrate how this modification interfaces with nuclear phospholipids to orchestrate chromatin-remodeling events.