title: Epigenetic regulation of BDNF expression via the scaffolding protein RACK1.
abstract: 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.
authors.affiliation: Ernest Gallo Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
authors.forename: Dao-Yao
authors.initials: DY
authors.lastname: He
authors.forename: Jérémie
authors.initials: J
authors.lastname: Neasta
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: 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
chemical_list: 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
references.citation: Nat Genet. 2000 Jul;25(3):338-42
references.pmid: 10888886
references.citation: Neuropsychiatr Dis Treat. 2008 Feb;4(1):161-76
references.pmid: 18728821
references.citation: Cell Signal. 2000 Apr;12(4):195-204
references.pmid: 10781926
references.citation: FASEB J. 2006 Nov;20(13):2420-2
references.pmid: 17023388
references.citation: Annu Rev Biochem. 2003;72:609-42
references.pmid: 12676795
references.citation: J Biol Chem. 1999 May 21;274(21):14909-17
references.pmid: 10329691
references.citation: J Neurosci. 2004 Nov 17;24(46):10542-52
references.pmid: 15548669
references.citation: Mol Cell Biol. 2002 Apr;22(7):2345-65
references.pmid: 11884618
references.citation: Mol Pharmacol. 2007 Aug;72(2):350-8
references.pmid: 17456785
references.citation: Nat Rev Genet. 2009 May;10(5):295-304
references.pmid: 19308066
references.citation: Nature. 2003 Dec 4;426(6966):579-84
references.pmid: 14654845
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19199-204
references.pmid: 19052240
references.citation: Nat Rev Mol Cell Biol. 2004 Dec;5(12):959-70
references.pmid: 15573134
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4882-7
references.pmid: 19225110
references.citation: Mol Cell Biol. 2006 Jun;26(11):4041-51
references.pmid: 16705158
references.citation: Nature. 1998 May 28;393(6683):386-9
references.pmid: 9620804
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5710-5
references.pmid: 11943848
references.citation: J Biol Chem. 1999 Sep 17;274(38):27039-46
references.pmid: 10480917
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8802-6
references.pmid: 8415610
references.citation: Mol Pharmacol. 2002 Aug;62(2):272-80
references.pmid: 12130678
references.citation: Nat Struct Mol Biol. 2004 Oct;11(10):957-62
references.pmid: 15334071
references.citation: Nat Genet. 1998 Jun;19(2):187-91
references.pmid: 9620779
references.citation: Mol Neurobiol. 2009 Feb;39(1):37-49
references.pmid: 19156544
references.citation: J Neurosci. 2005 Jan 19;25(3):619-28
references.pmid: 15659598
references.citation: Trends Biochem Sci. 1999 May;24(5):181-5
references.pmid: 10322433
references.citation: Nat Rev Neurosci. 2005 Feb;6(2):108-18
references.pmid: 15654323
references.citation: Neuron. 1998 Apr;20(4):727-40
references.pmid: 9581764
references.citation: Cell Mol Life Sci. 2010 Jan;67(1):73-88
references.pmid: 19756388
references.citation: Eur J Neurosci. 2009 Apr;29(7):1311-22
references.pmid: 19519623
references.citation: J Biol Chem. 2002 Jun 21;277(25):22581-9
references.pmid: 11964397
references.citation: J Biol Chem. 2002 Dec 20;277(51):49888-95
references.pmid: 12359736
references.citation: Science. 2003 Oct 31;302(5646):890-3
references.pmid: 14593184
references.citation: Mol Cell Biol. 2009 Mar;29(6):1626-34
references.pmid: 19114558
references.citation: J Neurosci Res. 2007 Feb 15;85(3):525-35
references.pmid: 17149751
references.citation: Mol Cell. 2007 Jan 26;25(2):207-17
references.pmid: 17244529
references.citation: Science. 2003 Oct 31;302(5646):885-9
references.pmid: 14593183
references.citation: Nat Cell Biol. 2008 Nov;10(11):1324-32
references.pmid: 18836437
references.citation: J Neurochem. 2009 Jun;109(5):1375-88
references.pmid: 19476549
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2328-32
references.pmid: 14983009
references.citation: J Biol Chem. 2003 Mar 14;278(11):9630-8
references.pmid: 12524444
references.citation: Genomics. 2007 Sep;90(3):397-406
references.pmid: 17629449
references.citation: Neuron. 2006 Feb 2;49(3):341-8
references.pmid: 16446138
references.citation: Brain Res. 2006 Jan 5;1067(1):1-12
references.pmid: 16376315
references.citation: J Neurosci. 2009 Oct 28;29(43):13494-502
references.pmid: 19864562
references.citation: J Neurosci. 2008 Oct 15;28(42):10576-86
references.pmid: 18923034
references.citation: Neuron. 1998 Apr;20(4):709-26
references.pmid: 9581763
references.citation: J Biol Chem. 2004 Jul 23;279(30):31357-64
references.pmid: 15140893
references.citation: Nat Biotechnol. 1999 Jul;17(7):676-82
references.pmid: 10404161
references.citation: Prog Neurobiol. 2006 Feb;78(2):117-34
references.pmid: 16457939
references.citation: Mol Biol Cell. 2009 Mar;20(6):1629-38
references.pmid: 19158384
references.citation: Neurosci Biobehav Rev. 2010 Nov;35(2):157-71
references.pmid: 19914287
references.citation: J Biol Chem. 2009 Jul 24;284(30):20263-74
references.pmid: 19423701
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134B(1):93-103
references.pmid: 15666411
references.citation: J Neurosci. 2004 Jun 16;24(24):5603-10
references.pmid: 15201333
references.citation: Annu Rev Neurosci. 2001;24:677-736
references.pmid: 11520916
references.citation: J Biol Chem. 2001 May 4;276(18):14896-901
references.pmid: 11278757
references.citation: Neurobiol Learn Mem. 2008 Mar;89(3):312-23
references.pmid: 17942328
references.citation: Mol Pharmacol. 2002 Dec;62(6):1261-73
references.pmid: 12435793
references.citation: Nat Med. 2004 Nov;10(11):1187-9
references.pmid: 15502840
references.citation: Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):839-43
references.pmid: 8302854
references.citation: Neuron. 1993 Mar;10(3):475-89
references.pmid: 8461137
references.citation: Trends Cell Biol. 2005 Jun;15(6):295-302
references.pmid: 15953547
references.citation: J Biol Chem. 2003 Feb 14;278(7):4806-12
references.pmid: 12473678