Epigenetic regulation of BDNF expression via the scaffolding protein RACK1.
Scaffolding proteins are major contributors to the spatial and temporal orchestration of signaling cascades and hence cellular functions. RACK1 is a scaffolding protein that plays an important role in the regulation of, and cross-talk between, various signaling pathways. Here we report that RACK1 is a mediator of chromatin remodeling, resulting in an exon-specific expression of the brain-derived neurotrophic factor (BDNF) gene. Specifically, we found that following the activation of the cAMP pathway, nuclear RACK1 localizes at the promoter IV region of the BDNF gene by its association with histones H3 and H4, leading to the dissociation of the transcription repressor methyl-CpG-binding protein 2 (MeCP2) from the promoter, resulting in the acetylation of histone H4. These chromatin modifications lead to the activation of the promoter and to the subsequent promoter-controlled transcription of BDNF exon IV. Our findings expand our knowledge regarding the function of scaffolding proteins such as RACK1. Furthermore, this novel mechanism for the regulation of exon-specific expression of the BDNF gene by RACK1 could have implications on the neuronal functions of the growth factor including synaptic plasticity, learning, and memory.
He
Dao-Yao
DY
Ernest Gallo Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
Neasta
Jérémie
J
Ron
Dorit
D
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018899:CpG Islands; D044127:Epigenesis, Genetic; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000737:chemistry; D006801:Humans; D007858:Learning; D008568:Memory; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics*; D015398:Signal Transduction
D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; C497392:MECP2 protein, human; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; C550931:RACK1 protein, rat; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D019204:GTP-Binding Proteins
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