A proteomic approach identifies SAFB-like transcription modulator (SLTM) as a bidirectional regulator of GLI family zinc finger transcription factors
| Autor: | Jiang Wu, Xiaoming Zhan, Zilai Zhang, Bong-Woo Kim |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Proteomics
0301 basic medicine animal structures Cellular differentiation Mice Transgenic Nerve Tissue Proteins Biology Biochemistry Mice 03 medical and health sciences Nuclear Matrix-Associated Proteins Zinc Finger Protein Gli3 Transcription (biology) GLI3 Animals Hedgehog Proteins Gene Knock-In Techniques Sonic hedgehog Molecular Biology Transcription factor Gene Editing Zinc finger integumentary system 030102 biochemistry & molecular biology Activator (genetics) Matrix Attachment Region Binding Proteins Cell Biology Chromatin Cell biology 030104 developmental biology embryonic structures biology.protein CRISPR-Cas Systems Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 294:5549-5561 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.007018 |
| Popis: | In Sonic hedgehog (SHH) signaling, GLI family zinc finger (GLI)-mediated diverse gene transcription outcomes are strictly regulated and are important for SHH function in both development and disease. However, how the GLI factors differentially regulate transcription in response to variable SHH activities is incompletely understood. Here, using a newly generated, tagged Gli3 knock-in mouse (Gli3(TAP)), we performed proteomic analyses and identified the chromatin-associated SAFB-like transcription modulator (SLTM) as a GLI-interacting protein that context-dependently regulates GLI activities. Using immunoprecipitation and immunoblotting, RT-quantitative PCR, and ChIP assays, we show that SLTM interacts with all three GLI proteins and that its cellular levels are regulated by SHH. We also found that SLTM enhances GLI3 binding to chromatin and increases GLI3 repressor (GLI3R) form protein levels. In a GLI3-dependent manner, SLTM promoted the formation of a repressive chromatin environment and functioned as a GLI3 co-repressor. In the absence of GLI3 or in the presence of low GLI3 levels, SLTM co-activated GLI activator (GLIA)-mediated target gene activation and cell differentiation. Moreover, in vivo Sltm deletion generated through CRISPR/Cas9-mediated gene editing caused perinatal lethality and SHH-related abnormal ventral neural tube phenotypes. We conclude that SLTM regulates GLI factor binding to chromatin and contributes to the transcriptional outcomes of SHH signaling via a novel molecular mechanism. |
| Databáze: | OpenAIRE |
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