title: An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a.
abstract: Many low-penetrance breast cancer susceptibility loci are found to be located in non-protein-coding regions, suggesting their involvement in gene expression regulation. We identified the human/rat-conserved breast cancer susceptibility locus MCS5A/Mcs5a. This locus has been shown to act in a non-mammary cell-autonomous fashion through the immune system. The resistant Mcs5a allele from the Wistar-Kyoto (WKy) rat strain consists of two non-protein-coding genetic elements that must be located on the same chromosome to elicit the phenotype. In this study, we show the presence of a conserved higher order chromatin structure in MCS5A/Mcs5a located in between the synthetically interacting genetic elements. The looped elements are shown to be bound by CTCF and cohesin. We identify the downregulation of Fbxo10 expression in T cells as a strong candidate mechanism through which the interacting genetic elements of the resistant Mcs5a allele modulate mammary carcinoma susceptibility. Finally, we show that the human MCS5A polymorphisms associated with breast cancer risk are located at both sides of the looped structure and functionally interact to downregulate transcriptional activity, similar to rat Mcs5a. We propose a mechanistic model for MCS5a/Mcs5a in which a CTCF-mediated insulator loop encompassing the TOMM5/Tomm5 gene, resides in between and brings into closer physical proximity the synthetically and functionally interacting resistant genetic variants.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Bart M G
authors.initials: BM
authors.lastname: Smits
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Traun
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Devries
authors.forename: Ann
authors.initials: A
authors.lastname: Tran
authors.forename: David
authors.initials: D
authors.lastname: Samuelson
authors.forename: Jill D
authors.initials: JD
authors.lastname: Haag
authors.forename: Michael
authors.initials: M
authors.lastname: Gould
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D015536:Down-Regulation; D044783:F-Box Proteins / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D038101:Insulator Elements; D019169:Jurkat Cells; D008325:Mammary Neoplasms, Experimental / Q000235:genetics; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D012097:Repressor Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D024363:Transcription Initiation Site; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D044783:F-Box Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; D000097722:Cohesins; C000619697:CTCF protein, human