title: Regulatory elements required for the activation and repression of the protocadherin-alpha gene cluster.
abstract: The mouse protocadherin (Pcdh) -α, -β, and -γ gene clusters encode more than 50 protein isoforms, the combinatorial expression of which generates vast single-cell diversity in the brain. At present, the mechanisms by which this diversity is expressed are not understood. Here we show that two transcriptional enhancer elements, HS5-1 and HS7, play a critical role in Pcdhα gene expression in mice. We show that the HS5-1 element functions as an enhancer in neurons and a silencer in nonneuronal cells. The enhancer activity correlates with the binding of zinc finger DNA binding protein CTCF to the target promoters, and the silencer activity requires the binding of the REST/NRSF repressor complex in nonneuronal cells. Thus, the HS5-1 element functions as a neuron-specific enhancer and nonneuronal cell repressor. In contrast, the HS7 element functions as a Pcdhα cluster-wide transcription enhancer element. These studies reveal a complex organization of regulatory elements required for generating single cell Pcdh diversity.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Kehayova
authors.forename: Kevin
authors.initials: K
authors.lastname: Monahan
authors.forename: Weisheng
authors.initials: W
authors.lastname: Chen
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004742:Enhancer Elements, Genetic; D017353:Gene Deletion; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D009457:Neuroglia / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional; D012097:Repressor Proteins / Q000378:metabolism; D059010:Single-Cell Analysis; D013269:Stochastic Processes
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D015820:Cadherins; C000619698:Ctcf protein, mouse; D017931:DNA Primers; D020033:Protein Isoforms; D012097:Repressor Proteins