title: A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells.
abstract: The transcription of neuron-specific genes must be repressed in nonneuronal cells. REST/NRSF is a transcription factor that restricts the expression of many neuronal genes through interaction with the neuron-restrictive silencer element at the promoter level. PAHX-AP1 is a neuronal gene that is developmentally up-regulated in the adult mouse brain but that has no functional NRSE motif in its 5' upstream sequence. Here, we report that the transcription factor AP4 and the corepressor geminin form a functional complex in which SMRT and histone deacetylase 3 are recruited. The functional complex represses PAHX-AP1 expression in nonneuronal cells and participates in regulating the developmental expression of PAHX-AP1 in the brain. This complex also serves as a transcriptional repressor of DYRK1A, a candidate gene for Down's syndrome. Furthermore, compared with that in normal fetal brain, the expression of AP4 and geminin is reduced in Down's syndrome fetal brain at 20 weeks of gestation age, at which time premature overexpression of dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) is observed. Our findings indicate that AP4 and geminin act as a previously undescribed repressor complex distinct from REST/NRSF to negatively regulate the expression of target genes in nonneuronal cells and suggest that the AP4-geminin complex may contribute to suppressing the precocious expression of target genes in fetal brain.
authors.affiliation: Department of Obstetrics and Gynecology, Research Institute of Medical Sciences and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju 501-190, South Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Jeong
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kee
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
authors.forename: Nack Sung
authors.initials: NS
authors.lastname: Kim
authors.forename: Yoon Ha
authors.initials: YH
authors.lastname: Kim
authors.forename: Jong-Keun
authors.initials: JK
authors.lastname: Kim
authors.forename: Kyu Youn
authors.initials: KY
authors.lastname: Ahn
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004314:Down Syndrome / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005333:Fetus / Q000378:metabolism; D064248:Geminin; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017930:Genes, Reporter; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D001616:beta-Galactosidase / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D064248:Geminin; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D056985:Nuclear Receptor Co-Repressor 2; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D001616:beta-Galactosidase; D000097603:Dyrk Kinases; C577995:GMNN protein, human; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; C429045:Phyhip protein, mouse; C404766:REPIN1 protein, human; C012589:trichostatin A