title: CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice.
abstract: The closely linked human protocadherin (Pcdh) α, β, and γ gene clusters encode 53 distinct protein isoforms, which are expressed in a combinatorial manner to generate enormous diversity on the surface of individual neurons. This diversity is a consequence of stochastic promoter choice and alternative pre-mRNA processing. Here, we show that Pcdhα promoter choice is achieved by DNA looping between two downstream transcriptional enhancers and individual promoters driving the expression of alternate Pcdhα isoforms. In addition, we show that this DNA looping requires specific binding of the CTCF/cohesin complex to two symmetrically aligned binding sites in both the transcriptionally active promoters and in one of the enhancers. These findings have important implications regarding enhancer/promoter interactions in the generation of complex Pcdh cell surface codes for the establishment of neuronal identity and self-avoidance in individual neurons.
authors.affiliation: Key Laboratory of Systems Biomedicine, Ministry of Education, Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Guo
authors.forename: Kevin
authors.initials: K
authors.lastname: Monahan
authors.forename: Haiyang
authors.initials: H
authors.lastname: Wu
authors.forename: Jason
authors.initials: J
authors.lastname: Gertz
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Varley
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000076246:CCCTC-Binding Factor; D015820:Cadherins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000737:chemistry*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry*; D018899:CpG Islands; D004247:DNA / Q000737:chemistry*; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D012097:Repressor Proteins / Q000378:metabolism*; D013269:Stochastic Processes; D014158:Transcription, Genetic; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D015820:Cadherins; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D000097722:Cohesins; C000619697:CTCF protein, human; C429022:RAD21 protein, human